INTRODUÇÃO: A Hipersensibilidade do seio carotídeo (HSC) é a exacerbação do reflexo normal e foi definida como ocorrência de pausa ventricular 3 segundos ou redução da pressão arterial sistólica (PAS) 50 mmHg em resposta à massagem do seio carotídeo (MSC). Fenômeno relacionado à idade, raramente diagnosticado em pacientes com menos de 50 anos, tem recebido especial atenção como causa de síncope e quedas inexplicadas nos idosos, nas últimas décadas, com relatos de taxas de prevalências superiores a 45%. Entretanto, ainda não estão claras as implicações diagnósticas da HSC na síncope, com resultados controversos na literatura. OBJETIVOS: Determinar a prevalência da HSC em pacientes com sintomas de síncope e pré-síncope e comparar com indivíduos assintomáticos. Correlacionar a resposta à MSC com a rigidez aórtica e os parâmetros anatômicos e funcionais carotídeos. MÉTODOS: Foram avaliados em estudo prospectivo 99 pcts sintomáticos, com síncope ou pré-síncope a esclarecer (idade média de 69 anos, 41,4% homens), e 66 pcts assintomáticos para controle (idade média de 73 anos, 34,8% homens). Excluíram-se pacientes com cardiopatia estrutural ou com contraindicações para MSC. A MSC foi realizada no ponto com maior impulsão carotídea por 5 segundos, com o registro contínuo e não invasivo da pressão arterial (PA) e eletrocardiograma, com o paciente em postura ortostática a 70º. Foram consideradas respostas anormais: cardioinibitória (CI): assistolia 3 segundos e vasodepressora (VD): redução da PAS 50 mmHg. O índice da rigidez arterial foi obtido por meio de medida da velocidade de onda de pulso carotídeo-femoral (VOP). As características anatômicas e funcionais da carótida foram determinadas por medidas de diâmetro, espessura íntima-média carotídea (EIMC) e índice de distensibilidade. RESULTADOS: Não foram constatadas diferenças nas respostas obtidas na MSC entre os grupos, com 67,7% e 60,6% de respostas fisiológicas; 24,2% e 25,8% de respostas CI; 8,1% e 13,6% de respostas VD em grupo sintomáticos e assintomáticos, respectivamente (p=0,466). Não foram observadas correlações entre a resposta à MSC, tanto com a VOP como com a EMIC, a distensibilidade e o diâmetro carotídeo. CONCLUSÕES: 1- A prevalência de HSC e resposta hemodinâmica à MSC em pacientes com sintomas de síncope e pré-síncope foram semelhantes a pacientes assintomáticos provenientes da mesma instituição, com características clínicas semelhantes. 2- Não foi observada correlação significativa entre a rigidez arterial, medida por meio da VOP, EIMC, distensibilidade e diâmetro carotídeo e a resposta à MSC / The carotid sinus hypersensitivity (CSH) is the exaggeration of the normal reflex and was defined by occurrence of asystole 3 seconds or fall in systolic BP 50 mmHg in response to carotid sinus massage (CSM). Phenomenon related to age, rarely diagnosed in patients younger than 50 years, has gained importance as a cause of syncope and unexplained falls in the elderly in recent decades with reported prevalence rates above 45%. However, the correlation between CSH and syncope etiology is still controversial. OBJECTIVE: To determine the prevalence of CSH in patients with syncope and near syncope of unknown origin and compare with asymptomatic individuals; to evaluate the correlation between CSM responses and arterial stiffness. METHODS: We studied prospectively 99 symptomatic pts with syncope or near syncope (mean age 69 years, 41.4% men) and 66 asymptomatic controls (mean age 73 years, 34.8% men). Patients with significant structural heart disease or with contraindications to CSM were excluded. The CSM was performed at the point with maximal carotid pulsation, for 5 seconds with continuous and noninvasive blood pressure and electrocardiogram recording at 70° in upright posture. Were considered abnormal responses: cardioinhibitory (CI): asystole 3 seconds and vasodepressor (VD): decrease in systolic BP 50 mmHg. The aortic stiffness was determined by aortic pulse wave velocity (PWV). The anatomical and functional characteristics of the carotid were determined by measurements of diameter, intima-media thickness (IMT) and distensibility index. RESULTS: There were no differences in the responses obtained in the CSM between the groups, being 67.7 % and 60.6% physiological responses, 24.2% and 25.8% CI responses and 8.1% and 13.6% VD responses in symptomatic and asymptomatic groups, respectively (p=0.466). There were no correlations between response to the CSM with VOP, IMT, carotid diameter and distensibility. CONCLUSIONS: The prevalence of CSH in patients with symptoms of syncope and near syncope was similar to asymptomatic patients from the same institution with similar clinical characteristics. There was no significant correlation between arterial stiffness, measured by PWV, IMT, carotid diameter and distensibility with the response to CSM

This thesis deals with the methodology of use of whole-body impedance cardiography for evaluation of pulse wave velocity. The first three chapters explain selected hemodynamic properties of the arterial system related to the issue of pulse wave propagation. At the same time the ordinary methods for estimation, its disadvantages and merits has been summarized. Points at issue of whole-body impedance evaluation methodology for pulse wave velocity are researched in second part of this thesis. In order that analysis the procedure for correct methodology has been determined. Particularly determination of reference proximal point for calculation of transit time towards aortic valve, and design and accuracy of transit distance measurement were discussed. Based on the obtained data, a calculation of representative pulse wave velocity to eight limb locations was performed.

No description available.

Les études épidémiologiques ont associé la rigidité artérielle au déclin cognitif et à la démence. Cependant ses effets sur la biologie du cerveau restent méconnus. Dans notre première étude, en utilisant un nouveau modèle murin de rigidité artérielle, nous avons voulu caractériser les effets de la rigidité artérielle sur le cerveau indépendamment de l’âge et de l’augmentation de la pression artérielle. Les résultats indiquent que la rigidité artérielle altère la régulation du flux sanguin cérébral et l'intégrité du système vasculaire cérébral, endommageant la barrière hémato-encéphalique et conduisant à des déficits cognitifs. Le débit sanguin cérébral est altéré au repos ainsi qu’au niveau de ses mécanismes de régulation comme l’autorégulation cérébrale, le couplage neurovasculaire et la fonction endothéliale. Dans notre deuxième étude nous avons cherché à comprendre le dimorphisme sexuel pour la rigidité artérielle et ses conséquences sur le cerveau dans le même modèle. Nos résultats montrent que la rigidité artérielle entraîne une altération du couplage neurovasculaire et de la réactivité vasculaire dépendante de l’endothélium chez les souris mâles mais pas chez les souris femelles reproductives. Chez les souris ovariectomisées, cette protection a été supprimée, mais a été restaurée par un traitement à l’œstradiol. Dans la troisième étude, nous avons voulu étudier la possibilité de prévenir la rigidité artérielle et ses effets subséquents sur le cerveau. Pour cette étude, nous avons utilisé la vitamine K (VK) (phylloquinone ou VK1 et la ménaquinone-4 ou MK-4) vu son action anti-calcifiante et ses effets bénéfiques sur les fonctions cognitives observés dans d’autres modèles animaux et chez l’homme. Cette étude a démontré que la VK améliore les fonctions cognitives et rétablit le débit sanguin cérébral au repos et diminue la calcification vasculaire. Les capacités d’apprentissage s’amplifient avec l’apport de la VK alimentaire et la concentration de la VK au cerveau. Ces études permettent une meilleure compréhension de la rigidité artérielle et démontrent le potentiel de la VK et le traitement hormonal par l’œstradiol dans la prévention de ses effets sur le cerveau. Cependant, d’autres études sont nécessaires pour déterminer tous les mécanismes impliqués dans la protection du cerveau par la VK et l’œstradiol. / Epidemiological studies have associated arterial stiffness with cognitive decline and dementia. However, its effects on the brain biology remain unknown. In our first study, using a new murine model of arterial stiffness, we wanted to characterize the effects of arterial stiffness on the brain independently of age and pressure. Our results indicate that arterial stiffness impairs the regulation of cerebral blood flow and the integrity of the cerebrovascular system, damaging the blood-brain barrier and leading to cognitive deficits. Arterial stiffness results in significant alterations in resting cerebral blood flow and mechanisms regulating cerebral blood flow such as cerebral autoregulation, neurovascular coupling, and endothelial function. In our second study we sought to understand sexual dimorphism in arterial stiffness and its consequences on the brain in the same model. Our results show that arterial stiffness leads to impaired neurovascular coupling and endothelial-dependent vascular reactivity in male mice but not in female reproductive mice. In ovariectomized mice this protection was suppressed but was restored by estradiol treatment. In the third study, we wanted to study the possibility of preventing arterial stiffness and its subsequent effects on the brain. In this study, we used vitamin K (phylloquinone or VK1 and menaquinone-4 or MK-4) for its anti-calcifying action and its beneficial effects on the cognitive functions observed in other animal models and in humans. This study demonstrated that VK prevent cognitive impairment in part by restoring the resting cerebral blood flow but also by preventing vascular calcification. Learning abilities increase with the contribution of food VK, which in turn correlates with the VK content of the brain. These studies provide a better understanding of arterial stiffness and demonstrate the potential of VK and hormone therapy with estradiol in preventing its effects on the brain. However, further studies are needed to determine all the mechanisms involved in the brain protection by VK and estradiol.

La rigidité artérielle fait référence à la perte d'élasticité principalement dans les grandes artères telles que l'aorte et les carotides. On sait que la rigidité artérielle chroniquement élevée contribue à des modifications vasculaires cérébrales telles que des lésions parenchymateuses de la substance blanche cérébrale via une modification du flux sanguin cérébral. En particulier, parmi les structures perfusées par les artérioles fournies par les artères cérébrales antérieure et moyenne, le corps calleux, la capsule interne, la corona radiata et le faisceau longitudinal supérieur sont les plus vulnérables à l’hypoperfusion. Des études antérieures ont montré que l'augmentation de la rigidité artérielle évaluée par la vitesse de l'onde de pouls carotide-fémorale (cfPWV) est associée à une diminution de l'anisotropie fractionnelle (FA) et à une augmentation de la diffusivité radiale (RD). On a émis l'hypothèse que les altérations au niveau des régions vulnérables de la substance blanche (par exemple, le corps calleux, la capsule interne) seraient probablement liées à la démyélinisation axonale. Cependant, bien que la RD a auparavant été corrélée avec la démyélinisation axonale, l'imagerie de diffusion est principalement aveugle à la myéline. En revanche, l'imagerie par transfert de magnétisation (MT) est une métrique adaptée pour estimer la fraction volumique de myéline. De plus, malgré leur sensibilité à l'organisation des fibres axonales, les métriques de tenseur de diffusion (DTI) telles que les FA et RD manquent de spécificité pour la microstructure tissulaire individuelle. Des modèles microstructuraux plus avancés tels que l’imagerie dispersion et de l'orientation des neurites (NODDI) fournissent des outils pour disséquer les changements microstructuraux derrière les mesures DTI. Dans l'article 1, nous avons utilisé les métriques de DTI et basé sur le MT pour examiner de plus près l'interaction entre la rigidité artérielle et la microstructure de la substance blanche chez les personnes âgées de plus de 65 ans. Nous avons constaté que la mesure de référence absolue de la rigidité artérielle, la mesure de la vitesse de l'onde de pouls entre l’artère fémorale et carotidienne (cfPWV) était associée à l'organisation axonale des fibres telle que reflétée par FA et RD plutôt qu'à la démyélinisation dans les régions de la substance blanche qui ont été précédemment désignées comme vulnérables à rigidité artérielle. Dans notre deuxième article, nous avons utilisé le modèle NODDI pour approfondir la relation entre le cfPWV et l'organisation axonale. Nos résultats ont montré que la cfPWV est positivement associée à la diffusion extracellulaire de l'eau (ISOVF), ce qui signifie que la rigidité artérielle peut entraîner une dispersion axonale, diminuant la contrainte de directionnalité de l'eau le long des axones. En outre, nous avons constaté que la rigidité artérielle est associée à une augmentation de la densité des fibres dans le corps calleux tel que mesuré par l’ICVF, ce qui pourrait suggérer que les personnes à risque plus élevé de déclin cognitif présentent des mécanismes compensatoires précoces avant l'apparition de signes cliniques de déclin cognitif. Compte tenu de la forte interaction entre la rigidité artérielle et le déclin à la fois de la structure du cerveau et des fonctions cérébrales, on peut envisager un avenir meilleur où la rigidité artérielle sera mesurée dans la pratique clinique de routine afin d'identifier les personnes à risque plus élevé d’altérations de la substance blanche et de déclin cognitif. Ces personnes pourraient bénéficier de programmes multi-interventionnels visant à préserver la structure et la fonction cérébrale. Un seuil de rigidité artérielle est donc nécessaire pour identifier ces individus. L'article 3 présente la première estimation d'une valeur seuil de cfPWV à laquelle la rigidité artérielle affecte la microstructure de la substance blanche chez les personnes âgées. Nos résultats suggèrent que le seuil actuel de 10 m / s de cfPWV adopté par la Société européenne d'hypertension n'est peut-être pas le seuil optimal pour diviser les individus en groupes à risque neurovasculaire élevé et faible. Au lieu de cela, nos résultats suggèrent que le seuil de cfPWV est plus susceptible d’être autour de 8,5 m / s. Bien que le cfPWV offre une excellente valeur pronostique chez les adultes, il reste malheureusement principalement utilisé dans la recherche en raison du besoin d'experts formés pour cette mesure. À l'inverse, la mesure de l'indice de rigidité artérielle (ASI) à l'aide de la pléthysmographie suscite un intérêt croissant ces dernières années en raison de son approche simple à utiliser. Dans l'article 4, nous avons étudié la relation entre l'ASI et la pression pulsée (PP) qui est une mesure indirecte de la rigidité artérielle, avec la FA et les lésions de la substance blanche chez les participants du UK Biobank. Nous avons constaté que la PP prédit mieux l'intégrité de la substance blanche que l'ASI chez les participants de moins de 75 ans. Cette constatation implique que l'ASI de la pléthysmographie ne semble pas être une mesure fiable de la rigidité artérielle chez les personnes âgées. Des études futures sont évidemment nécessaires pour valider nos résultats, en particulier notre seuil de cfPWV. Une fois ce seuil validé, nous envisageons un avenir radieux où la mesure du cfPWV sera non seulement utilisée pour aider à sélectionner les personnes qui bénéficieraient le plus d'un programme multi-interventionnel visant à préserver l'intégrité cérébrale, mais pourrait également être utilisée pour surveiller l’effet d’une telle intervention. / Arterial stiffness refers to the loss of elasticity mainly in large arteries such as the aorta and carotids. Chronically elevated arterial stiffness contributes to cerebrovascular changes such as cerebral white matter parenchymal damage via an alteration of cerebral blood flow. In particular, among the areas perfused by arterioles supplied by the anterior and middle cerebral arteries, the corpus callosum, the internal capsule, the corona radiata, and the superior longitudinal fasciculus are more vulnerable to cerebral hypoperfusion. Previous studies have shown that increased arterial stiffness as assessed by carotid-femoral pulse wave velocity (cfPWV) is associated with a decrease in fractional anisotropy (FA) and increase in radial diffusivity (RD). It was hypothesized that alterations in vulnerable white matter tracts (e.g. corpus callosum, internal capsule) are likely to be related to axonal demyelination. However, while RD was previously correlated with axonal demyelination, diffusion imaging is mostly blind to myelin. In contrast magnetization transfer (MT) imaging is a tailored metric to estimate myelin volume fraction. Moreover, despite their sensitivity to axon fiber organization, diffusion tensor metrics (DTI) such as FA and RD lack specificity for individual tissue microstructure. More advanced microstructural model such as neurite orientation dispersion and density imaging (NODDI) give tools to disecate the microstructural changes behind DTI metrics. In Article 1 we used DTI and MT based metric to look more closely at the interplay between arterial stiffness and white matter microstructure in older adults > 65 years old. We found that the gold standard measure of arterial stiffness, the measure of carotid femoral pulse wave velocity (cfPWV) was associated with axonal fiber organization as reflected by FA and RD rather than demyelination in the white matter regions that have been previously denoted as vulnerable to arterial stiffness. In our second Article, we used the NODDI model to take a further look at the relationship between cfPWV and axonal organization. Our results showed that cfPWV is positively associated with the extracellular water diffusion (ISOVF) which means that arterial stiffness may result in axonal dispersion, lessening the constraint of water directionality along axons. In addition, we found that arterial stiffness is associated with increased fibers density in the corpus callosum as measured by ICVF which could suggest that individuals at higher risk for cognitive decline demonstrate early compensatory mechanisms before the appearance of clinical signs of cognitive decline. Considering the strong interplay between arterial stiffness and decline both in brain structure and function, one can envision a bright future where arterial stiffness would be measured in routine clinical practice in order to identify individuals at higher risk for white matter changes and cognitive decline. Such individuals could benefit from multi-interventions programs aiming to preserve brain structure and function. A cut-off arterial stiffness is thus needed to identify these individuals. Article 3 presents the first estimation of an cfPWV cut-off value at which arterial stiffness impacts the white matter microstructure in older adults. Our results suggested that the current 10 m/s cfPWV cut-off adopted by the European Society of Hypertension may not be the optimal threshold to split individuals into high and low neurovascular risk groups. Instead, our findings suggest that the cfPWV cut-off is more likely to fall around 8.5 m/s. While cfPWV provides excellent prognostic value in adults, it remains unfortunately mainly used in research due to the need of trained experts. Conversely, measure of arterial stiffness index (ASI) using plethysmography is getting increased interest in the last few years due to its simple-to-use approach. In article 4, we investigated the relationship between ASI and pulse pressure (PP), an indirect measure of arterial stiffness, with FA and white matter lesions in participants of the UK Biobank. We found that PP better predicts white matter integrity compared to ASI in participants younger than 75 years old. This finding implies that ASI from plethysmography may not be a reliable measure of arterial stiffness in older adults. Future studies are obviously needed to validate our results, in particular our cfPWV cut-off. Once such cut-off will be validated, the present author envision a bright future where measure of cfPWV will not only be used to help selecting individuals that would most benefit from a multi intervention program aiming to preserve brain integrity, but could also be used to monitor the effect of such intervention.

For most children, occult vascular damage is minimal and has a slow rate of progression likely due to the existence of healthy lifestyles and the prevalence of preventative behaviours. However, there is evidence to suggest a marked increase in the prevalence of traditional and emerging cardiovascular risk factors in children with chronic inflammatory conditions due to the common aetiology pathways of inflammation and atherosclerosis. In the current cross-sectional study, a comprehensive vascular assessment was conducted on 21 children with various chronic inflammatory conditions including juvenile idiopathic arthritis (JIA), cystic fibrosis (CF), type I diabetes mellitus (T1DM) and inflammatory bowel disease (IBD) (CIC, 12.7 ± 2.3 years) compared to 9 healthy, age and sex- matched controls (CON, 13.1 ± 1.8 years). B-mode ultrasound images were used to assess carotid artery intima media thickness (cIMT) as well as local arterial stiffness through measurement of compliance and distensibility with the use of concurrent applanation tonometry. Whole-body arterial stiffness was measured by assessing pulse wave velocity (PWV) between the carotid and dorsalis pedis arteries. A brachial flow mediated dilation (FMD) test was implemented to assess endothelial function of the brachial artery. Twelve hour-fasted blood samples were collected and analyzed for blood lipids and an acute inflammatory marker, C-reactive protein (CRP). There were no group differences in cIMT (p=0.18), distensibility (p=0.40), compliance (p=0.88), whole body PWV (p=0.74) or LDL- cholesterol (p=0.99). The CIC group demonstrated significantly lower FMD when iii compared to CON (p=0.01). There were no group differences in inflammatory levels, as indicated by concentration of CRP (p=0.63). Sub-analyses revealed similar cIMT, distensibility, compliance, PWV and LDL levels between children with JIA (n=11, 12.6 ± 2.9 years), CON (n=9, 13.1 ± 1.8 years) and the other inflammatory conditions (INFL, n=10, 12.4 ± 1.7 years). Both JIA and INFL reported lower FMD when compared to CON (p=0.04). INFL had lower BMI compared to JIA and CON (p=0.02). The primary findings from this study suggest that arterial structure is similar between children with a CIC and their healthy peers; however, arterial function, as indicated by FMD (%), was reduced in the CIC group. This finding is essential in that it helps to identify an area for targeted intervention and/or prevention of future CV events as endothelial dysfunction is known to be an early event in the pathophysiology of atherosclerosis. / Thesis / Master of Science (MSc)

Sex and gender considerations are influential on psychosocial and physiological determinants of cardiovascular health in individuals with and without stroke. The first study of this thesis explored gender-based differences in exercise self-efficacy, outcome expectations for exercise and motivation for exercise post-stroke. Gender identity was assessed using the Bem Sex-Role Inventory-12 and a gender role index was created using established gender-related roles. The Self-Efficacy for Physical Activity Scale was used to assess self-efficacy for exercise, the Short Outcome Expectations for Exercise Scale assessed outcome expectations for exercise and a Relative Autonomy Index was calculated to assess motivation for exercise. We found that masculine gender identity was associated with highest ratings of exercise self-efficacy, whereas feminine gender identity was related to the lowest exercise self-efficacy [F(3, 9)=5.36, p<0.05]. Gender identity was not associated with outcome expectations [F(3,8)=0.86, p=0.50) nor motivation for exercise [F(3,4)=0.67, p=0.61)]. Additionally, there were no associations between gender roles and self-efficacy (n=13, r=0.10, p=0.73), outcome expectations (n=13, r=-0.13, p=0.68), or motivation for exercise (n=8, r=0.09, p=0.83). The second study of this thesis examined the associations between global cognitive function (Montreal Cognitive Assessment, MoCA), arterial stiffness (carotid-femoral pulse wave velocity) and sex, and between global cognitive function, walking capacity (6-Minute Walk Test, 6MWT) and sex in older male and female adults with and without stroke. There was no association between global cognition and arterial stiffness, and sex did not moderate this association. However, cognitive function was positively associated with 6MWT, and with the addition of sex, Sex*6MWT, age and history of stroke, explained 21% of the variance of the MoCA score. Our findings provide insight into the importance of sex-and gender-based considerations in clinical research and may inform future larger-scaled studies aiming to increase the generalizability of their findings to males and females and individuals of all gender identities. / Thesis / Master of Science Rehabilitation Science (MSc) / The roles that an individual undertakes, and how they see themselves and are seen by others may be related to exercise participation. In addition, a person’s biological makeup may impact their health and ability to think. In the first study of this thesis, we found that individuals with stroke seeing themselves as women had lower beliefs about their abilities to exercise, but their beliefs about the benefits of exercise or their motivation for exercise were similar to individuals who identify as men. There were no differences in beliefs about exercise abilities, outcomes, or motivation between individuals with stroke who took on masculine vs. feminine roles. In the second study, we found that walking distance, but not arterial health, was related to the ability to think in males and females. Overall, this work provides information of the importance of biological, social roles and behaviours on health.

Motivation - The burden of cardiovascular diseases (CVD) is increasing in developing countries worldwide, but even more so in sub-Saharan Africa. Due to rapid urbanisation, black populations experience lifestyle changes (e.g. unhealthy diet, increased access to alcohol and tobacco) that predispose them to increased obesity and cardiovascular risk. In this study, attention will be given to cardiovascular alterations, specifically arterial calcification, in lean and overweight/obese women nearing or already experiencing menopause. These include elevated blood pressure, large artery stiffness (indicated by increased central pulse pressure (cPP)) and carotid intima-media thickness (CIMT). Other factors linked to arterial calcification include the level of obesity as well as low bone mineral density. Ectopic calcification plays a significant role in cardiovascular morbidity and mortality, especially in renal failure patients, osteoporotic and elderly women. Factors contributing to the development and progression of arterial calcification include calciotropic hormones and altered bone metabolism, particularly in older postmenopausal women. This is due to the lack of protective effects of oestrogen against vascular alterations and bone loss after menopause. Previous studies have shown that increased bone resorption indicated by elevated levels of c-telopeptide of type I collagen (CTX), parathyroid hormone (PTH), low 25- hydroxycholecalciferol (25(OH)D3) and parathyroid hormone to 25-hydroxycholecalciferol ratio (PTH:25(OH)D3) are independently linked to arterial stiffening, CIMT and vascular calcification. Knowledge on the contribution of altered bone metabolism and associated calciotropic hormones on cardiovascular health in Africans is limited. Previous studies on ectopic calcification in South Africans focused on men and renal failure patients. This study will explore the possible role of altered calcium regulation and bone metabolism in the development of arterial calcification and CVD in older African women. Aim - The aim of this study was to investigate the associations of brachial and central pressures and CIMT with PTH, PTH:25(OH)D3 and CTX, a marker of bone resorption, in lean and overweight/obese African women older than 46 years. Methodology - This sub-study forms part of the Prospective Urban Rural Epidemiology (PURE) study. A total of 434 urban and rural women older than 46 years were included in the study. Women infected with the human immunodeficiency virus (HIV) were excluded from the study. The study was reviewed and approved by the Ethics Committee of the North-West University (Potchefstroom campus) and all participants signed an informed consent form prior to enrolment into the project. Field workers administered demographic, general health and physical activity questionnaires in the participants’ home language. Anthropometric measurements included weight, height and waist circumference, while body mass index (BMI) was calculated in kg/m2. Cardiovascular measurements included brachial and central systolic blood pressure (SBP), brachial diastolic blood pressure (DBP), brachial and central pulse pressure (PP) as well as CIMT and carotid cross-sectional wall area (CSWA). Blood pressure measurements were performed on the right arm with the participant in the sitting position. Blood was drawn after an overnight fasting period. We performed biochemical analyses from serum and plasma samples for follicle stimulating hormone (FSH), PTH, 25(OH)D3, and CTX. HIV testing was performed according to standardised procedures. Since interactions existed for BMI with regards to associations of CIMT and cPP with PTH:25(OH)D3, the study population was divided into the lean (BMI <25 kg/m2) and overweight/obese (BMI ≥25 kg/m2) groups. We performed independent T-tests to compare means and used the chi-square test to compare proportions. Single and multiple regression analyses were performed to investigate the associations of markers of vascular structure and function with CTX and calciotropic hormones. Results - In this study, 90% of the women displayed an FSH concentration exceeding the cut-off value of 35 mIu/mL, indicating a postmenopausal state. When comparing lean and overweight/obese African women, we found that lean women had higher levels of CTX and 25(OH)D3 (both p<0.001), while the overweight/obese group was older (p=0.007) and presented with higher PTH and PTH:25(OH)D3 levels (both p<0.001). Brachial and central pressures did not differ between the groups (p≥0.23), except for DBP being higher in the overweight/obese group (p=0.017). Overweight/obese women had higher CIMT (p<0.001) and CSWA (p=0.001) as compared to their lean counterparts. A larger proportion of lean women smoked (63%) and self-reported on alcohol use (37%) than overweight/obese women (41% and 18%, respectively) (both p<0.001). Forty-one percent of overweight/obese women used antihypertensive medication, opposed to 25% in the lean group (p=0.001). In multivariate regression analyses, an independent positive association existed between CIMT and PTH:25(OH)D3 (R2=0.22; β=0.26; p=0.003) in lean women. In the overweight/obese group independent positive associations were confirmed between brachial SBP and PTH (p=0.013) and CTX (p=0.038), and between DBP and PTH (p=0.030). Brachial PP and central SBP remained positively associated with CTX (p=0.016 and p=0.024, respectively), while cPP was independently associated with PTH:25(OH)D3 (R2=0.20; β=0.17; p=0.017) and CTX (R2=0.20; β=0.17; p=0.025). Conclusion - Our results indicate that in older African women, large artery structure and function are associated with calciotropic hormones and bone resorption, suggesting that altered bone metabolism and associated calciotropic hormones play a role in the development of vascular calcification. The different associations in lean and overweight/obese women suggest different mechanisms at work regarding arterial calcification in states of low and high adiposity. These findings need confirmation in larger prospective and experimental studies. / MSc (Physiology), North-West University, Potchefstroom Campus, 2014

Motivation - The burden of cardiovascular diseases (CVD) is increasing in developing countries worldwide, but even more so in sub-Saharan Africa. Due to rapid urbanisation, black populations experience lifestyle changes (e.g. unhealthy diet, increased access to alcohol and tobacco) that predispose them to increased obesity and cardiovascular risk. In this study, attention will be given to cardiovascular alterations, specifically arterial calcification, in lean and overweight/obese women nearing or already experiencing menopause. These include elevated blood pressure, large artery stiffness (indicated by increased central pulse pressure (cPP)) and carotid intima-media thickness (CIMT). Other factors linked to arterial calcification include the level of obesity as well as low bone mineral density. Ectopic calcification plays a significant role in cardiovascular morbidity and mortality, especially in renal failure patients, osteoporotic and elderly women. Factors contributing to the development and progression of arterial calcification include calciotropic hormones and altered bone metabolism, particularly in older postmenopausal women. This is due to the lack of protective effects of oestrogen against vascular alterations and bone loss after menopause. Previous studies have shown that increased bone resorption indicated by elevated levels of c-telopeptide of type I collagen (CTX), parathyroid hormone (PTH), low 25- hydroxycholecalciferol (25(OH)D3) and parathyroid hormone to 25-hydroxycholecalciferol ratio (PTH:25(OH)D3) are independently linked to arterial stiffening, CIMT and vascular calcification. Knowledge on the contribution of altered bone metabolism and associated calciotropic hormones on cardiovascular health in Africans is limited. Previous studies on ectopic calcification in South Africans focused on men and renal failure patients. This study will explore the possible role of altered calcium regulation and bone metabolism in the development of arterial calcification and CVD in older African women. Aim - The aim of this study was to investigate the associations of brachial and central pressures and CIMT with PTH, PTH:25(OH)D3 and CTX, a marker of bone resorption, in lean and overweight/obese African women older than 46 years. Methodology - This sub-study forms part of the Prospective Urban Rural Epidemiology (PURE) study. A total of 434 urban and rural women older than 46 years were included in the study. Women infected with the human immunodeficiency virus (HIV) were excluded from the study. The study was reviewed and approved by the Ethics Committee of the North-West University (Potchefstroom campus) and all participants signed an informed consent form prior to enrolment into the project. Field workers administered demographic, general health and physical activity questionnaires in the participants’ home language. Anthropometric measurements included weight, height and waist circumference, while body mass index (BMI) was calculated in kg/m2. Cardiovascular measurements included brachial and central systolic blood pressure (SBP), brachial diastolic blood pressure (DBP), brachial and central pulse pressure (PP) as well as CIMT and carotid cross-sectional wall area (CSWA). Blood pressure measurements were performed on the right arm with the participant in the sitting position. Blood was drawn after an overnight fasting period. We performed biochemical analyses from serum and plasma samples for follicle stimulating hormone (FSH), PTH, 25(OH)D3, and CTX. HIV testing was performed according to standardised procedures. Since interactions existed for BMI with regards to associations of CIMT and cPP with PTH:25(OH)D3, the study population was divided into the lean (BMI <25 kg/m2) and overweight/obese (BMI ≥25 kg/m2) groups. We performed independent T-tests to compare means and used the chi-square test to compare proportions. Single and multiple regression analyses were performed to investigate the associations of markers of vascular structure and function with CTX and calciotropic hormones. Results - In this study, 90% of the women displayed an FSH concentration exceeding the cut-off value of 35 mIu/mL, indicating a postmenopausal state. When comparing lean and overweight/obese African women, we found that lean women had higher levels of CTX and 25(OH)D3 (both p<0.001), while the overweight/obese group was older (p=0.007) and presented with higher PTH and PTH:25(OH)D3 levels (both p<0.001). Brachial and central pressures did not differ between the groups (p≥0.23), except for DBP being higher in the overweight/obese group (p=0.017). Overweight/obese women had higher CIMT (p<0.001) and CSWA (p=0.001) as compared to their lean counterparts. A larger proportion of lean women smoked (63%) and self-reported on alcohol use (37%) than overweight/obese women (41% and 18%, respectively) (both p<0.001). Forty-one percent of overweight/obese women used antihypertensive medication, opposed to 25% in the lean group (p=0.001). In multivariate regression analyses, an independent positive association existed between CIMT and PTH:25(OH)D3 (R2=0.22; β=0.26; p=0.003) in lean women. In the overweight/obese group independent positive associations were confirmed between brachial SBP and PTH (p=0.013) and CTX (p=0.038), and between DBP and PTH (p=0.030). Brachial PP and central SBP remained positively associated with CTX (p=0.016 and p=0.024, respectively), while cPP was independently associated with PTH:25(OH)D3 (R2=0.20; β=0.17; p=0.017) and CTX (R2=0.20; β=0.17; p=0.025). Conclusion - Our results indicate that in older African women, large artery structure and function are associated with calciotropic hormones and bone resorption, suggesting that altered bone metabolism and associated calciotropic hormones play a role in the development of vascular calcification. The different associations in lean and overweight/obese women suggest different mechanisms at work regarding arterial calcification in states of low and high adiposity. These findings need confirmation in larger prospective and experimental studies. / MSc (Physiology), North-West University, Potchefstroom Campus, 2014

La paroi vasculaire est composée de cellules endothéliales, de cellules musculaires lisses vasculaires et de fibroblastes qui sont entourés d’un réseau structuré et complexe de protéines, la matrice extracellulaire. Les interactions réciproques entre la matrice et les cellules sont nécessaires à la croissance, au développement et au remodelage. Or, différents contextes pathologiques entraînent la perturbation de ces interactions et sont la cause de différentes maladies. Au cours du vieillissement, la matrice extracellulaire des grosses artères élastiques est modifiée. Ainsi, les lamelles élastiques de la paroi vasculaire se fragmentent ou sont dégradées, en plus de calcifier. De même, l’accumulation de protéines plus rigides, comme le collagène, entraîne le développement de la fibrose. Ces modulations vont mener à l’augmentation de la rigidité artérielle et au développement de l’hypertension systolique isolée. En utilisant un modèle animal de calcification basé sur l’inhibition d’une protéine anti-calcifiante, la matrix Gla protein, avec la warfarine, nous avons étudié la séquence des événements impliqués dans le développement de l’hypertension systolique isolée. Nous avons observé l’activation précoce et transitoire de MMP-9, puis du TGF-ß, précédant la modulation phénotypique des cellules musculaires lisses vasculaires, la calcification et les changements hémodynamiques. L’inhibition des métalloprotéinases et du TGF-ß a permis de prévenir la calcification vasculaire. Nous avons également étudié le rôle joué par une enzyme de la matrice extracellulaire, la transglutaminase 2, dans le développement de la calcification associée à l’hypertension systolique isolée. À l’aide d’un nouvel inhibiteur de cette enzyme, qui a permis de prévenir la calcification, nous avons établi que la transglutaminase était un élément clé dans le processus pathologique. Ces travaux ont permis de démontré l’intérêt de nouvelles avenues thérapeutiques ciblant directement la matrice extracellulaire, particulièrement la MMP-9, le TGF-ß et la transglutaminase 2, dans la pathologie de l’hypertension systolique isolée. / Within the vascular wall, endothelial cells, vascular smooth muscle cells and fibroblasts are surrounded by a complex and structured network of secreted macromolecules and proteins, the extracellular matrix. Reciprocal interactions between matrix and cells are essential to growth, development and remodeling. However, in pathological situations, the alteration of these interactions can lead to the development of different disease states. With aging, the extracellular matrix of large elastic arteries undergoes several modifications. The elastic lamellae are fragmented or degraded and calcify, whereas more rigid proteins, such as collagen, accumulate and cause fibrosis. These alterations are associated with the stiffening of arteries, which results in the development of isolated systolic hypertension. In order to study the sequence of events occuring in the development of this pathology, we used an animal model of calcification based on the inhibition of a matrix Gla protein, which physiologically prevents calcification, with warfarin. We observed an acute and transient activation of MMP-9 and TGF-ß, which preceded the phenotypic modulation of vascular smooth muscle cells, calcification and changes to hemodynamic parameters. Moreover, the inhibition of MMPs and TGF-ß prevented vascular calcification. We also studied the role of an extracellular matrix enzyme, transglutaminase 2, in the development of vascular calcification associated with isolated systolic hypertension. Using a novel inhibitor of this enzyme, we established a key role for transglutaminase 2 in this pathological process. This thesis demonstrates the relevance of directly targeting the extracellular matrix, particularly MMP-9, TGF-ß and transglutaminase 2, as a novel therapeutic avenue in the treatment of isolated systolic hypertension.