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Ph.D., Faculty of Health Sciences, University of the Witwatersrand, 2011 / Contemporary notions of the adverse effects of blood pressure (BP) incorporate the increasingly recognised damaging effects of not only distending pressure (indexed by mean arterial pressure-MAP) but also pulse pressure (PP) (the difference between systolic and diastolic BP) on the cardiovascular system. Although the factors which determine brachial artery PP are similar to those affecting central (aortic) PP (PPc), some factors may affect central PP preferentially, and thus PP calculated from brachial artery BP measurement may not closely reflect the PP that accounts for cardiovascular damage. In order that therapeutic strategies are developed that modify PPc independent of distending pressures, there is considerable interest in the pathophysiological mechanisms that explain increases in PPc. In this regard, aortic PP is comprised of the forward or incident pressure component (P1), which is largely determined by stroke volume, aortic compliance or stiffness and aortic diameter; and the augmented pressure component (AP), which is determined by wave reflection. Whilst currently employed antihypertensive agents may modify AP independent of distending pressures, there is little evidence to indicate a similar effect on the structural aortic changes responsible for P1. Although changes in AP as opposed to P1 largely account for age-related increases in PPc across the adult lifespan in normotensives, the relative contribution of AP and P1 to PPc in communities with a high prevalence of uncontrolled BP is unknown. In 1015 randomly recruited participants (range 16-88 years) from a community sample, 37.7% of whom had uncontrolled BP, I demonstrated that independent of MAP and other confounders, P1 contributes as much as AP to age-related increases in PPc and to variations in PPc across the adult lifespan. As no previous studies have assessed the relationship between P1 and cardiovascular damage, in 503 randomly recruited participants from a community with a high prevalence of uncontrolled BP, the relative contribution of P1 and AP to increases in left ventricular mass index (LVMI) was subsequently evaluated. In this regard, independent of distending pressures, P1 was associated with LVMI, highlighting the need to understand the iii potential mechanisms which contribute to P1. Could the pathophysiological mechanisms that determine hypertension account for the contribution of P1 to PPc? In this regard, I evaluated the potential role of three mechanisms. First, in 635 randomly selected participants with 24-hour urine samples that met with pre-specified quality control criteria, I provide the first data to demonstrate that urinary sodium-to-potassium ratio (an index of Na+ and K+ intake) is independently associated with PPc, but not brachial PP independent of distending pressures, a relationship that could be accounted for by changes in both AP and P1, but not aortic pulse wave velocity. Second, I explored the possibility that low grade inflammation as indexed by circulating high-sensitivity C-reactive protein concentrations (hs-CRP) may contribute toward PPc and the component pressures. In this regard, although hs-CRP has been associated with changes in central haemodynamics in small study samples, in a large community sample of participants these findings could not be reproduced. However, in that study the community had a low prevalence of risk-related hs-CRP concentrations. In 836 randomly recruited participants from a population sample with a high prevalence of risk-related hs-CRP concentrations (~57%), although on univariate analysis I showed that hs-CRP was strongly associated with PPc and the component pressures, this relationship did not persist with adjustments for confounders. Last I evaluated the potential contribution of genetic factors toward PPc and the component pressures. Although three prior studies had demonstrated heritability of PPc, AP and P1, two studies failed to adjust for MAP and a third assessed the heritability in females only. In none of these studies was the contribution of aortic PWV to the heritability estimates of PPc, AP and P1 assessed. In 568 participants from 183 nuclear families, I showed that independent of MAP, multivariable adjusted PPc, AP, P1 and PWV aggregated in families and were inherited. However, adjustments for aortic PWV failed to modify the extent of intrafamilial aggregation and heritability of PPc, AP, or P1. In conclusion, in the present thesis I have advanced our understanding of the mechanisms responsible for increases in PPc. In this regard, I provide evidence to suggest that independent of distending pressures and stroke volume, P1 accounts for a significant iv proportion of the age-related increases in PPc and the variability of PPc across the adult lifespan in communities with a high prevalence of uncontrolled hypertension; that P1 contributes substantially to the relationship between PPc and LVMI; and that PPc and both the AP and P1 component pressures are associated with a urinary index of salt intake as well as genetic factors, but not to an index of low-grade inflammation. These findings suggest that to achieve optimal cardiovascular risk reduction in hypertension, therapeutic strategies that target the aortic structural changes responsible for P1 are likely to be required across the adult lifespan, and that this therapy must in-part address the impact of salt intake and genetic factors, but not necessarily low-grade inflammation on PPc.

Genome-wide association studies have revealed an association between variation at the SLC4A7 locus and blood pressure. SLC4A7 encodes the electroneutral Na+/HCO3 - co-transporter NBCn1 which regulates intracellular pH (pHi) in a range of tissues, including vascular smooth muscle and endothelium. Notably, the SLC4A7 knockout mouse has been shown to have an altered blood pressure phenotype. This thesis presents a functional study of variants at this locus in primary cultures of vascular smooth muscle and endothelial cells. There were genotype-dependent differences in DNA-nuclear protein interactions by formaldehyde-assisted isolation of regulatory elements, electrophoretic mobility shift assays and DNA pulldown assays. Subsequently, there were also genotypedependent differences in SLC4A7 expression level and NBCn1 availability at the plasma membrane. In turn, SLC4A7 genotype is associated with Na+/HCO3 --dependent steady-state pHi and recovery from intracellular acidosis. The genotypic effect on pHi regulation was independent of the calcineurin activity, or the amino acid substitution E326K resulting from a missense polymorphism. However, in the presence of Na+/H+ exchange activity, the SLC4A7 genotypic effect on net base uptake and steady-state pHi was detected only in vascular smooth muscle cells but not endothelial cells. The finding of a genotypic influence on SLC4A7 expression and pHi regulation in vascular smooth muscle cells provide an insight into the molecular mechanism underlying the association of variation at the SLC4A7 locus with blood pressure.

Introduction: Hypertension is a complex disease that affects about 40% of adults worldwide, and is a major risk factor for cardiac hypertrophy and heart failure. Abnormal calcium handling plays a key role in hypertension and cardiovascular disease. In order to function normally cells of the cardiovascular system need to keep intracellular Ca2+ levels under tight control. This is achieved by a number of Ca2+ handling proteins including the plasma membrane Ca2+-ATPase (PMCA). Recent genome wide association studies have shown that single nucleotide polymorphisms in ATP2B1, the gene encoding PMCA1, are strongly linked with hypertension risk. Hypothesis: PMCA1 plays an important role in regulation of blood pressure and protection against hypertension and cardiac hypertrophy. Aims: This thesis aims to examine whether there is a link between PMCA1 and blood pressure regulation, and the development of hypertension. It also aims to determine the impact this link may have on cardiac structure and function. Methods and Results: To study the role of PMCA1, a global PMCA1 heterozygous knockout mouse (PMCA1Ht) was used. Under basal conditions, 3 month old PMCA1Ht mice had about 50% reduction in PMCA1 protein expression compared to the wild type (WT) mice. PMCA1Ht and WT mice had similar blood pressure as measured by tail-cuff method. To study the mice under hypertensive stress conditions, 3 month old PMCA1Ht and WT mice were infused via minipump with angiotensin II. Upon angiotensin II treatment, PMCA1Ht mice showed a significantly greater increase in systolic and diastolic pressure compared to WT mice. Angiotensin II also induced vascular remodelling, with PMCA1Ht mice having greater media thickness and cross sectional area than WT mice. Moreover, PMCA1Ht mice showed a significantly greater cardiac hypertrophic response than WT mice. On the other hand, cardiac function and heart rate were similar in PMCA1Ht and WT mice. While angiotensin II had no effect on PMCA1 expression in the heart, it significantly increased PMCA1 expression in the aortas of both WT and PMCA1Ht mice. More importantly, WT mice had significantly higher PMCA1 expression level than the PMCA1Ht mice treated with the same dose of angiotensin II. This suggests that PMCA1 plays a pivotal role in Ca2+ extrusion in the vasculature and that under stressful conditions PMCA1Ht mice are less able to respond to stress through a compensatory increase in PMCA1 expression, leading to increased intracellular Ca2+ concentration, which in turn leads to increased vascular contractility and increased blood pressure. Conclusion: This work provides evidence that PMCA1 is involved in blood pressure regulation and protects against the development of hypertension and cardiac hypertrophy.

Thesis (M Med (Family Medicine))--University of Limpopo, 2010. / Background: The state of Hypertension disease is universally under diagnosed and/or inadequately treated resulting in extensive target-organ damage and premature deaths. Therefore, sustainable and aggressive population-based programs for hypertension awareness, prevention, treatment, and control are keys of success in limiting this epidemic. The study aims to determine the Kang Adult population’s hypertension prevalence and the relationship between high blood pressure, anthropometric measures and their life style factors such as diet, use of tobacco products and alcohol consuming habits. Methodology: The study, a population based cross-sectional trial, was conducted on adult residents of Kang (18 year-old and above) from November to December 2008. Data was collected using the questionnaire, through physical measurements of weight, height and BP using a modified protocol based on World Health Organization (WHO) STEP wise instruments on chronic disease (Bonita, 2001). The sample consisted of 161 participants between 20 and 82 years of age. Results: Hypertension was observed in 31.6% of participants (95% CI: 24.6%-39.5%). With regard to the hypertension prevalence rate, no significant differences were observed between males and females (males 28.3% versus females 33.6%, p = 0.59). An elevated blood pressure was seen with significantly higher frequency in overweight group compared with the normal weight group (p = 0.029), in obese group compared x with the normal weight group (p = 0.002), and in obese group compared with the overweight group (p = 0.045). The study found no significant association between hypertension and use of tobacco products (p=0.46) or alcohol consumption (p=0.73), went in vigorous-intensity activity (p=0.22) and moderate-intensity activity that causes large increases in breathing, or heart rate for at least 10 minutes continuously (p=0.70). Conclusions: It is concluded that hypertension is a common problem in adult Kang population, with a prevalence of 31.6%. Hypertension prevalence was found to be associated with anthropometric measurements such as overweight and obesity. No significant association between hypertension and use of tobacco products, alcohol consumption, vigorous-intensity and moderate-intensity activities that cause increases in breathing or heart rate for at least 10 minutes continuously. However, the present study had the limitation of a small sample size. Further studies are needed to clarify the hypertension magnitude throughout the country, with large samples.

Thesis (M.S.)--University of Delaware, 2007. / Principal faculty advisor: David G. Edwards, Dept. of Health, Nutrition, and Exercise Sciences. Includes bibliographical references.

Thesis (D.M.A.)--Louisiana State University, 2002. / Includes bibliographical references.

This thesis work presents the analysis of Oscillometric blood pressure pulse waveform under different pressure points (Systolic, Mean Arterial, and Diastolic Pressures). Pulse waveforms' characteristics were determined from the waveforms at three different pressures and are compared for subjects at three different age groups. Estimation of blood pressure using a morphology based approach was done by using the change of pulse waveform characteristics at different pressure points. Pulse waveforms' characteristics that were obtained from pulse waveforms are utilized to estimate SBP, MAP, and DBP. The estimates obtained with pulse morphology based technique are compared with a BP measurement device and Maximum Amplitude Algorithm. Maximum slope of the pulse was also used for blood pressure estimation. The effect of movement and breathing on proposed method and MAA were compared and it was observed that breathing artifacts affect less the proposed method.