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

Sachant que l’Athérosclérose commence durant l’enfance par des marqueurs subcliniques, cette étude explore l’association entre l’indice de masse corporelle (IMC) et l’élastographie vasculaire non-invasive (NIVE) des artères carotides communes chez les enfants. On compare aussi les techniques de mesure de l’intima-média (IMT) des artères carotides en se basant sur le mode-B et la radiofréquence (RF) chez les enfants avec IMC normal et élevé. Il s’agit d’une étude prospective effectuée entre 2005 et 2011. Les paramètres de « NIVE » ont été comparés pour deux groupes d’IMC (normal et élevé) de 60 enfants respectivement, faisant tous partie de la cohorte de l’étude QUebec Adipose and Lifestyle Investigation in Youth (QUALITY). Les paramètres de NIVE incluent la contrainte axiale cumulative (CAS) en %, la translation axiale cumulative (CAT) en mm. L’épaisseur de l’intima-média est calculée selon trois méthodes : logiciel «M’ath-Std» (mode-B), « echotracking » des signaux de RF et probabilité de distribution des signaux de RF sur la plateforme NIVE. Une analyse ANOVA et corrélation Pearson ont été effectuées sur le logiciel SAS version 9.3. Une corrélation intra-class (ICC) a été effectuée sur un logiciel MedCalc version 17.2. L’âge moyen était 11,4 ans pour le groupe IMC normal et 12 pour le groupe IMC élevé. Cinquante-huit pourcent étaient des garçons dans le groupe IMC normal et 63% dans le groupe IMC élevé. Les deux groupes étaient différents selon l’âge, stade de Tanner, tension artérielle (systolique et diastolique), et LDL mais similaire pour le sexe. En contrôlant pour les variables confondantes, la CAS n’est pas différente entre les deux groupes. La CAT est plus basse chez les enfants avec IMC normal (CAT=0.51 +/-0.17 mm pour le groupe « IMC normal » et 0.67+/-0.24 mm pour le groupe « IMC élevé » (p<0.001)). Il y a une très faible corrélation entre les trois techniques de mesure d’IMT ICC=0,34 (95% intervalle de confiance 0,27-0,39). L’IMT est significativement plus élevé dans le groupe d’enfants « IMC élevé ». Mode-B (0.55 mm « IMC normal » vs. 0.57 mm « IMC élevé »; p=0.02); IMT RF (0.45 mm « IMC normal » vs. 0.48 mm « IMC élevé »; p=0.03) et IMT probabilité de distribution des signaux RF (0.32 mm « IMC normal » vs. 0.35 mm « IMC élevé »; p=0.010). La NIVE montre une différence significative dans la CAT de l'artère carotide commune des enfants avec un IMC normal par rapport à l'IMC élevé. Des variations significatives de la mesure des IMT ont été observées entre les différentes techniques. Cependant, les enfants avec IMC élevé ont des valeurs IMT plus élevées, indépendamment de la méthode utilisée. Les deux marqueurs subcliniques peuvent être utilisés pour la stratification des enfants à risque de maladies cardiovasculaires. La même méthode devrait toujours être utilisée. / Knowing that cardiovascular disease risk factors are present in asymptomatic children, this study explores the association between non-invasive vascular elastography (NIVE) as a subclinical marker of atherosclerosis and obesity in children. In the absence of a gold standard, we also compare B-mode and Radiofrequency (RF) based ultrasound measurements of intima-media thickness (IMT) in children with normal and increased body mass index (BMI). This is a prospective study between 2005 and 2011. NIVE parameters and IMT of the common carotid artery were compared between 60 children with normal BMI and 60 children with increased BMI enrolled in the QUebec Adipose and Lifestyle Investigation in Youth cohort (QUALITY). NIVE parameters included cumulated axial strain (CAS) (%) and cumulated axial translation (CAT) in mm. The three methods of IMT measurements included M’ath Std (B-mode), RF echotracking system and RF probability distribution using NIVE platform. ANOVA analysis and Pearson correlation were calculated using SAS version 9.3. Intra-class correlation coefficient (ICC) and regression analysis was done on MedCalc software version 17.2. The mean age was 11.4 years for the normal BMI group and 12 years for the increased BMI group. Fifty-eight percent were boys in the normal BMI group and 63% in the increased BMI group. The two groups were significantly different with respect to age, Tanner stage, systolic and diastolic blood pressure and were similar with respect to sex. After controlling for confounders, the results show no difference in CAS between the two groups and a significantly lower CAT in the normal BMI group (CAT=0.51+/-0.17 mm for the normal BMI group and 0.67+/-0.24 mm for the increased BMI group (p<0.001)). There is a weak correlation among the three techniques. ICC=0.34 (95% confidence interval (CI): 0.27-0.39). There is however significantly increased IMT in children with increased BMI according to all three techniques. The results were as follow: for B-mode IMT (0.55 mm (normal BMI group) vs. 0.57 mm (increased BMI group); p=0.02); for RF echotracking IMT (0.45 mm (normal BMI group) vs. 0.48 mm (increased BMI group); p=0.03) and for RF probability distribution IMT (0.32 mm (normal BMI group) vs. 0.35 mm (increased BMI group); p=0.010).NIVE is a one-step technique for IMT and CAT measurement in children at risk. Significant IMT measurement variation is observed between the three techniques. However, children with increased BMI tend to have higher IMT values regardless of the technique. Both subclinical markers can be used for optimal stratification of children with cardiovascular disease risk factors. The same technique should be used throughout.

Objective: Despite the advanced therapy with statins, antithrombotics, and antihypertensive agents, the medical treatment of atherosclerotic disease is less than optimal. Therefore, additional therapeutic antiatherosclerotic options are desirable. This pilot study was performed to assess the potential antiatherogenic effect of the peroxisome proliferator-activated receptor-γ agonist pioglitazone in nondiabetic patients. Methods: A total of 54 nondiabetic patients were observed in a prospective, double-blind, placebo-controlled study. Patients were randomized to pioglitazone or placebo. The following efficacy parameters were determined by serial analyses: artery pulse wave analysis and carotid-femoral pulse wave velocity (PWV), static and dynamic retinal vessel function, and the common carotid intima-media thickness (IMT). The main secondary endpoint was the change in different biochemical markers. Results: After 9 months, no relevant differences could be determined in the two treatment groups in PWV (pioglitazone 14.3 ± 4.4 m/s vs. placebo 14.2 ± 4.2 m/s), retinal arterial diameter (pioglitazone 112.1 ± 23.3 μm vs. placebo 117.9 ± 21.5 μm) or IMT (pioglitazone 0.85 ± 0.30 mm vs. placebo 0.79 ± 0.15 mm). Additionally, there were no differences in the change in biochemical markers like cholesteryl ester transfer protein, lowdensity lipoprotein cholesterol, high-sensitivity C-reactive protein or white blood cell count. Conclusions : Treatment with a peroxisome proliferator-activated receptor-γ agonist in nondiabetic patients did not improve the function of large and small peripheral vessels (PPP Trial, clinicaltrialsregister. eu: 2006-000186-11).

Cardiovascular disease is the leading cause of death in the United States. Chronic short sleep duration is also a significant public health problem and has been linked to several markers and outcomes of cardiovascular disease. To date, inconsistency of assessments of sleep duration and insufficiency, use of covariates, and cardiovascular disease measurement across studies limits strong conclusions about the relationship between sleep duration, sleep insufficiency, and cardiovascular disease. The current study examined the association between sleep duration, sleep insufficiency, and a marker of preclinical coronary heart disease (i.e., carotid intima-media thickness) in a community sample using a cross-sectional design. Some evidence for a relationship between sleep duration and cIMT was found, with longer sleep duration predicting higher cIMT in some segments. Additionally, the interaction between sleep duration and sleep insufficiency was significant. However, neither of these effects were significant after adjusting for age and in some cases race/ethnicity, suggesting demographics may explain this association. Actigraphy and sleep diary duration assessments demonstrated significantly different correlations with cIMT in some segments, suggesting the nature of the assessment method may impact the strength or direction of the relationship between sleep duration and cIMT. Limitations and future directions are discussed.

Muito se conhece sobre os efeitos deletérios da poluição do ar, e a sua influência sobre a mortalidade e morbidade por problemas respiratórios e também por doenças cardiovasculares. Diversos métodos têm sido estudados no sentido de se avaliar as consequências da exposição aos poluentes atmosféricos sobre a saúde humana, bem como, tentar estabelecer os mecanismos que envolvem esta relação. Dados antropométricos, exames de imagem e marcadores laboratoriais têm sido utilizados no sentido de se investigar o desenvolvimento de doença aterosclerótica e, a partir daí, tentar estabelecer uma relação entre os fatores de risco, dentre eles, os poluentes atmosféricos e a aterogênese. Sabe-se que a medida ultrassonográfica da espessura da camada íntima - média das artérias carótidas (EIMC) - tem sido descrita como uma análise complementar de grande potencial na avaliação não invasiva da atividade inflamatória vascular, da gênese e do desenvolvimento da doença aterosclerótica, sendo considerado um preditor independente de risco para morbidade e mortalidade por causas cardiovasculares. Este projeto de pesquisa utilizou o banco de dados relativos ao estado de São Paulo do Estudo Longitudinal da Saúde do Adulto (ELSA-Brasil) e teve por objetivo investigar os possíveis efeitos da poluição atmosférica produzida pelo tráfego veicular na EIMC nos sujeitos incluídos neste projeto. A mensuração da exposição aos poluentes foi feita por meio de medidas indiretas utilizando-se a densidade de tráfego veicular dos locais georreferenciados (local de trabalho e domicílio), a distância da residência dos sujeitos do estudo em relação a vias de grande fluxo de veículos e, ainda, a distância percorrida no deslocamento dos sujeitos entre o domicílio e o local trabalho. Foi realizado um estudo de corte transversal com o modelo de regressão linear univariado e multivariado para se avaliar a possível correlação entre a exposição aos poluentes do ar e espessura da íntima média das carótidas (EIMC) / Air pollution has been well known to have deleterious effects, which leads to mortality and morbidity due to respiratory problems and cardiovascular diseases. Several methods have been used to evaluate the consequences of exposure to air pollutants on human health, to identify the mechanisms involving this relationship. Anthropometric data, imaging studies, and laboratory markers have been used to investigate the development of atherosclerotic disease and, based on this, we tried to identify the relationship between the risk factors, such as atmospheric pollutants and atherogenesis. Ultrasound measurement of the carotid intima-media thickness (CIMT) has been potentially described as a great complementary analysis in noninvasive assessment of vascular inflammatory activity, onset, and development of atherosclerotic disease, and is considered an independent predictor of risk for morbidity and mortality due to cardiovascular diseases. The database from the Longitudinal Study of Adult Health (ELSA-Brasil) in São Paulo was used in this study, to investigate the possible effects of air pollution produced by vehicular traffic in the CIMT of the subjects. The measurement of exposure to air pollutants was made through indirect measures of the density of vehicular traffic of georeferenced locations (work and home), the distance from the subjects\' residence to high traffic flow areas, as well as the distance covered during subjects\' commuting from their homes to workplace. A cross-sectional study using the univariate and multivariate linear regression models was conducted to evaluate the possible correlation between exposure to air pollutants and CIMT

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

Pre-eclampsia is associated with increased risk of cardiovascular disease (CVD) later in life. The ‘gold standard’ for estimating cardiovascular risk - ultrasound assessment of the common carotid artery intima-media thickness (CCA-IMT) - does not convincingly demonstrate this increased risk. The aim of this thesis was to examine whether high-frequency (22 MHz) ultrasound assessment of the individual CCA intima and media layers and calculation of the intima/media (I/M) ratio - can indicate the increased cardiovascular risk after pre-eclampsia. After validation of the method in premenopausal women with systemic lupus erythematosus (SLE) who have a recognized increased risk of CVD, women during and after normal and preeclamptic pregnancies were investigated. Assessment of the individual artery wall layers reliably demonstrated the increased cardiovascular risk in premenopausal women with SLE, while CCA-IMT did not. The artery wall layer dimensions in women with SLE were comparable to those of postmenopausal women without SLE and were 30 years older. Among the women with normal pregnancies negative changes to the artery wall later on in the pregnancy were seen in those with lower serum estradiol, older age, higher body mass index or higher blood pressure early in the pregnancy. About one year postpartum, both the mean intima thickness and the I/M ratio had improved, compared to values during pregnancy. These findings support the theory that normal pregnancy is a stress on the vascular system. Women who developed pre-eclampsia (mean age 31 years) had thicker intima layers, thinner media layers and higher I/M ratios, both at diagnosis and one year postpartum, than women with normal pregnancies, indicating increased cardiovascular risk. Women with a history of severe pre-eclampsia (mean age 44 years; mean 11 years since the last delivery) had thicker intima layers and higher I/M ratios than women with a history of normal pregnancies, indicating long-standing negative vascular effects. Assessment of individual CCA wall layers, but not of CCA-IMT, provided clear evidence of the well-known increased cardiovascular risk in women with SLE or pre-eclampsia. The method has the potential to become an important tool in reducing cardiovascular morbidity and mortality in these women through early diagnosis and intervention.

<p>In addition to the adverse effects of high blood pressure (HBP) on cardiovascular disease, HBP is also associated with increased risk of stroke, dementia, and neurocognitive dysfunction. Although aerobic exercise and dietary modifications have been shown to reduce blood pressure, no studies have examined the effects of a combined aerobic exercise and dietary intervention on neurocognition among individuals with HBP, a group at elevated risk for neurocognitive dysfunction. As part of a larger investigation, the ENCORE study, this study examined the effects of dietary modification alone and combined with aerobic exercise on neurocognitive function among individuals with HBP. One hundred twenty five individuals with high normal blood pressure were randomized to an aerobic exercise and dietary modification group (DASH + WM), dietary modification alone (DASH-A), or a usual care control group. Participants completed a battery of neurocognitive tests assessing executive function and vigilance at baseline and again following the four month intervention. Following the intervention, participants in the DASH + WM and DASH-A groups exhibited modest improvements in neurocognitive function relative to controls, and these changes appeared to be mediated by improved cardiovascular fitness and weight loss. A combined aerobic exercise and dietary intervention improves neurocognitive function among individuals with HBP.</p> / Dissertation

Thesis (Ph. D.)--University of Washington, 2003. / Vita. Includes bibliographical references (leaves 106-135).

Systemic lupus erythematosus (SLE) is an autoimmune, inflammatory disease characterized by autoantibody production and an activated type I interferon system. Cardiovascular disease (CVD) is as a major cause of morbidity and mortality. The aim of this thesis was to identify genetic risk factors for CVD in SLE. The role of T cells in regulation of the interferon-α (IFNα) production by plasmacytoid dendritic cells (pDCs) was also investigated.    In paper I, a thicker intima, thinner media and increased intima/media ratio was found in young premenopausal women with SLE compared to healthy controls indicating increased cardiovascular risk. As traditional ultrasound assessment of the common carotid intima-media thickness (CCA-IMT) in SLE has given conflicting results separate measurement of the intima and media can be a useful tool to identify SLE patients at increased risk of CVD.    In paper II, an association was demonstrated in SLE between a STAT4 risk allele and ischemic cerebrovascular disease and presence of anti-phospholipid antibodies (aPL). The association remained after adjustment for traditional CVD risk factors. A possible mechanism for this association is that the risk allele leads to increased production of aPL, which promotes thromboembolism.    In paper III, a genetic locus in IRF8 was identified to be associated to coronary heart disease (CHD) in SLE. The association remained after adjustment of other CHD risk factors.  Patients with the IRF8 risk variant had increased CCA-IMT, more carotid plaques and reduced frequency of circulating B cells. Weaker binding of nuclear protein to the risk allele was demonstrated, suggesting a regulatory function of the IRF8 risk variant.    In paper IV, activated T cells were found to strongly enhance the IFNα production by pDC stimulated with RNA-containing immune complexes via GM-CSF and IL-3. Activated SLE T cells enhanced the IFNα production to the same extent as T cells from healthy controls. This finding together with previous observations in SLE of increased levels of GM-CSF and IL-3 suggests that T cells contribute to the activated type I interferon system in SLE.    In conclusion, this thesis demonstrates that genetic predisposition is important for CVD in SLE and describes a new role for T cells in the pathogenesis of SLE.