Serum uric acid (SUA) is in many ways related to cardiovascular morbidity and mortality. In this thesis, the objectives were to (1) to review the role of SUA in cardiovascular diseases; (2) to study the effects of elevated SUA on vascular function in subjects with high cardiovascular risk; (3) to evaluate the prognostic significance of SUA and vascular function; (4) to study the effect of pharmacological reduction of SUA on vascular function. A literature review was performed at the beginning to summarise the key findings from epidemiological, cross-sectional, and interventional studies that examined the relationship of SUA with cardiovascular diseases, vascular dysfunction, and its associated pathophysiological mechanisms in vascular dysfunction. The results from available studies that evaluated the association of elevated SUA with vascular dysfunction are inconsistent. Therefore the role that elevated SUA plays in the pathogenesis of vascular dysfunction and cardiovascular diseases remains controversial. With this background information in mind, we performed a series of studies to give more evidence to the controversial areas. A cross-sectional study on subjects with high cardiovascular risk was first performed. The markers of vascular function assessed were brachial arterial flow-mediated dilation (ba-FMD), and nitroglycerin-mediated dilation (ba-NMD). It showed that elevation of SUA was independently associated with impairment of ba-NMD, but not with impairment of ba-FMD. This suggested that ba-NMD impairment may be part of the underlying mechanism in the vasculature by which elevated SUA increases the risk of adverse cardiovascular outcomes. To test the above hypothesis, the prognostic significance of SUA and ba-NMD was evaluated by conducting an analysis on the risk of developing major adverse cardiovascular events (MACE) in the above cohort. The outcome variables of MACE (acute coronary syndrome, myocardial infarction, congestive heart failure, stroke etc.) within the follow-up period were collected. The time-to-event analysis demonstrated that both SUA and ba-NMD independently predicted the development of MACE. The causal mediation analysis confirmed that ba-NMD was the mediator between elevated SUA and MACE. Finally, a randomised placebo-controlled trial was performed to assess the effect of pharmacological reduction of SUA on vascular function. A novel herbal agent “UricsilTM” was used as the active treatment. The SUA-lowering effect of UricsilTM was insignificant compared with placebo at 12 weeks. No significant change in vascular function (ba-FMD and ba-NMD) was observed following treatment. The key research finding in this thesis, which demonstrated that ba-NMD is a potential mediator between elevated SUA and MACE, is a novel one. Future clinical and experimental studies could be performed to further enhance our understanding of this potential mechanism. / published_or_final_version / Medicine / Master / Master of Philosophy

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Thesis (Ph. D.)--Oregon State University, 2000. / Typescript (photocopy). Includes bibliographical references. Also available via the World Wide Web.

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The present study sought to explore the functional changes that occur in the vasculature of HIV positive participants of African origin in Mthatha district of South africa which might lead to increased risk in their cardiovascular system. Available literature shows that arterial stiffness plays an important role in cardiovascular events such as stroke, vasculitis and myocardial infarction. Measurement of (aortic pulse wave velocity; PWV) provides some of the strongest evidence concerning the prognostic significance of large artery stiffening. This study was aimed at investigating the relationship between anthropometry, age, E-Selectin level, cytokine levels, haemodynamic variables, blood counts and blood lipid profile with pulse wave velocity. Some traditional cardiovascular risk factors such as alcohol, and smoking were also taken into account. This was a cross-sectional study comprising of 169 participants (62 males and 107 females). 63 were HIV negative (group A), 54 HIV positive on treatment (group B), and 52 were HIV positive not on treatment (group C). Pulse wave velocity (PWV) was assessed using the Sphygmocor Vx. Statistically, ANOVA was used for variables with normal distribution and non parametric tests were used for variables with skewed distribution. Notable significant differences were seen in the means of the following variables across all the 3 groups. The mean PWV value for group C (7.21±2.17) was greater than that for group B (6.84± 1.17) which in turn was more than group A (6.38±1.67); P=0.037. In participants who are HIV negative, In univariate analysis PWV correlated significantly with the following: Augmentation index; AIx (75): (r=0.850,p=0.004): Systolic aortic blood pressure; Spa: (r=0.635, p<.000); diastolic blood pressure; dbp: (r=0.436, p<0.000); aortic pulse pressure; Ppa: (r=0.472, p=0.000); Mean arterial pressure; MP: (r=0.446 p=<0.00) and age (r=0.606, p<0.000). In participants who are on HAART the following variables were positively correlated with PWV: Ppa: (r=0.338,p=0.012), MP: (r=0.400,p=0.400), monocytes (r=0.320,p=0.047). Neutrophils: (r=0.341,p=0.034), CD4: (r=-0.446,p=0.009). In participants who are HAART naïve and HIV positive the following correlated with PWV Spa: (r=0.369, p=0.012), MP: (r=0.400, r=0.003) Ppa: (r=0.338,p=0.012), waist to hip ratio: (r=0.319, p=0.037), platelets: (r=0.037, p=0.019), triglycerides: (r=0.490, p=0.002). With multiple linear regression Spa, age and triglycerides as the only independent and significant determinants of PWV among HIV negatives R2= 56.9% (adjusted R2=54.7%), model adjusted for gender, anthropometric parameters, HDL-C, TC, LDL-C, haematologic data, haemodynamic data, cytokines, smoking and alcohol. Only MP and waist circumference were identified as the most important and significant independent determinants of PWV in HIV positive participants not on treatment. Age, MP, HDL-C, and triglycerides were identified as the significant independent determinants of the variations of PWV in HIV positive participants on HAART. R2 =57 %(adjusted R2 =53.5%). Model adjusted for gender, anthropometric data, smoking, alcohol, cytokines, adhesion molecules, total cholesterol, LDL-C. Haematological data, CD4 count, and other haemodynamic parameters. For Aix(75) In HIV negatives the multiple linear regression model identified age (positive correlation), height (negative correlation), CD4 (positive correlation) and MP (positive correlation) as the independent and significant determinants of AIx (75) among HIV negatives. Spa and Age were independently and significantly associated with the variations of Aix(75) among HIV positives not on HAART. On the other hand height was negatively and significantly associated with Aix(75) amongst HIV positives not on HAART. After excluding confounding factors, height (negative correlation) age (positive correlation), MP (positive correlation, HDL-C (negative correlation), platelets (positive correlation) alcohol intake (excessive consummation associated with positive correlation) and TNFα (negative correlation) were identified as the independent and significant variables associated with increase in AIx(75) among HIV positive participants on HAART. Conclusion: This study showed that HIV infected patients with or without antiretroviral therapy have increase arterial stiffness which is associated with an increased cardiovascular risk. The sphygmocor is an accurate, non invassive and useful tool in the evaluation of arterial stiffness and its use in clinical practice should be encouraged. PWV and the augmentation index (AIx) are the two major non-invasive methods of assessing arterial stiffness. Life style modification should be incorporated into the management of HIV patients so as the continuous monitoring of their haematological and lipid profile.

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published_or_final_version / abstract / Medicine / Doctoral / Doctor of Philosophy

published_or_final_version / Nursing Studies / Master / Master of Nursing