The diabetic patient is subject to many complications in the event of poor control of blood glucose or blood pressure. Diabetic nephropathy is the leading cause of kidney dialysis in the developed world. Diabetic retinopathy is one of the leading causes of blindness in the United States. Cardiovascular diseases are the leading cause of morbidity in the United States. There are many different factors that predispose people to developing these conditions. Among these factors in a diabetic patient, hypertension has been shown to be strongly correlated with progression of micro and macrovascular complications. There are several antihypertensive treatment options for lowering blood pressure including angiotensin receptor blockers, angiotensin converting enzyme inhibitors, calcium channel blockers, beta adrenergic receptor blockers, and diuretics among others. By lowering blood pressure in diabetic patients comorbid with hypertension, complications arising from either condition have been shown to be reduced to a greater extent than can be explained with either normal blood pressure or blood glucose levels. However, there is mounting evidence that certain beta-adrenergic receptor blockers cause insulin desensitization, adverse lipid metabolism, and poor carbohydrate metabolism. Furthermore, hypertension is a complex disease process especially when considered from the perspective of the patient with diabetes. There are many possible underlying mechanisms for the hypertension and resulting complications, so it may be important for the prescribing physician to employ a combination of different classes of antihypertensive pharmaceuticals when treating their patients. Although some antihypertensive agents may cause some adverse effects in patients, they are usually very well tolerated, and attempts should be made to incorporate them into a treatment plan for preventing the onset of diabetic complications.

A dissertation submitted to the Faculty of Health Sciences, University of the Witwatersrand , Johannesburg, in partial fulfillment of the requirements for the degree of Master of Science (Medicine) in Human Genetics,2013 / Obesity and hypertension often occur together and are risk factors for cardio-metabolic disorders. Single nucleotide polymorphisms (SNPs) in the leptin (LEP) and leptin receptor (LEPR) genes have been shown to be associated with obesity and hypertension, but have not been well explored in African populations. The aims of this study were to determine the heritability estimates of anthropometric and blood pressure (BP) measures and leptin levels; to identify additional informative SNPs in and around the LEP and LEPR genes; and to examine the potential relationships between these SNPs and measures of obesity, hypertension and leptin levels in a black South African cohort. Participants from the African Programme on Genes in Hypertension (APOGH) with various anthropometric and BP measurements were genotyped for LEP and LEPR SNPs using the BeadXpress platform. Heritability estimates were determined using Statistical Analysis for Genetic Epidemiology (S.A.G.E.) software and relationships between LEP or LEPR SNPs and obesity, leptin levels and hypertension were assessed using SAS 9.3 and gPLINK vs2.050, taking into account family relationships, various confounders and correcting for multiple testing. The Bonferroni method was used to correct for multiple testing and P≤0.00076 was considered as statistically significant for SNP association tests. Seven-hundred-and-thirteen individuals were successfully genotyped and there were more women (66%) than men. The prevalence of obesity (42%) and hypertension (46%) were high in the sample. Significant heritability (h2 %, P<0.05) was noted for body weight (38%), body mass index (26%), waist (35%) and hip circumference (42%), waist-to-hip ratio (46%), skinfold thickness (44%), systolic (34%), diastolic (27%) and central systolic (33%) BP; but leptin levels were not significantly heritable (h2 %=15%, P=0.228). LEP rs17151914 (P=0.0002) and LEPR rs6690661 (P=0.0007) were significantly associated with leptin levels and diastolic BP, respectively, in women. The LEP rs17151913T-rs6956510G haplotype was associated with an increase in central systolic BP in women (P=0.012 with Bonferroni correction) whereas the LEPR rs2154381C-rs1171261T haplotype was associated with lower systolic BP in men (P=0.0359 with Bonferroni correction). LEP gene variants were significantly correlated with effects on leptin levels in women and the LEPR gene variants were significantly correlated with effects on diastolic BP also in women. These results indicate that further exploration of the role of genetic variation in the LEP and LEPR genes in obesity and hypertension in individuals of African ancestry is warranted.

MMed, Ophthalmology, Faculty of Health Sciences, University of the Witwatersrand / Aim To determine and document the demographic profile, clinical features, associations and clinical and visual outcomes in black African patients with idiopathic intracranial hypertension (IIH) attending St John Eye Hospital during 2006 and 2007. Method A retrospective descriptive study was conducted on black African IIH patients. Patient files and data of 21 of 32 IIH patients, seen in the Neuro-ophthalmology clinic at St John Eye Hospital over a two year period (2006 and 2007), were available and this study is based on these 21 patients. All 21 patients fulfilled the modified Dandy criteria for the diagnosis of IIH. Information obtained from files of the 21 patients were recorded on a data capture sheet. The demographics, initial (presenting) and final visual acuities and visual fields, initial and final clinical symptoms and signs, associations and treatment modalities were recorded on the data capture sheet. Visual and clinical outcomes were determined by comparing the final with the initial (presenting) symptoms and signs. The minimum follow-up period between the initial and the final visit was two months. Patients were regarded as legally blind if they had severe to profound visual acuity and/or visual field loss. Results All 21 patients were female and black African. Mean age was 31.2 ± 8.9 years (range 16 – 50 years). Mean period of follow up was 19.9 ± 20.1 months (range 2 – 77 months). 71.4% were obese. All patients presented with symptoms. The commonest presenting symptom was headache (90%) followed by visual loss (67%), transient visual obscurations (38%) and diplopia (29%). The results of the presenting signs were as follows: Seven eyes (17%) had visual acuity loss (most of which were mild [9.5%]), seven patients (33%) had abduction deficits, four patients (9.5%) had unilateral abnormal pupil reactions and all patients had papilloedema. Of the recorded associations seven patients (33%) were hypertensive, six (29%) were on contraception (two [9.5%] were on oral contraception) and two (9.5%) were taking prednisone prior to presentation. After the initial visit, all 21 vi IIH patients were treated with acetazolamide (Diamox) and weight loss was recorded in three patients (14%). Two patients (9.5%) had optic nerve sheath fenestrations (ONSF), two (9.5%) had lumbar-peritoneal shunts (LPS) and six (28.6%) had multiple lumbar punctures (LP’s). The outcome analysis was as follows: Symptoms in 19 patients (90%) improved but 16 patients (76%) still had papilloedema. Two patients (9.5%) had abduction deficits at the final visit. Visual acuity loss occurred in five eyes (12%) at the final visit compared to seven eyes (17%) at the initial visit (presentation). From the initial visit (presentation) to the final visit, visual acuity in seven eyes (16%) improved, 31 eyes (74%) remained stable and four eyes (10%) worsened. Although visual fields in 33 eyes (79%) improved from the initial to the final visit, 36 eyes (86%) still had visual field loss at the final visit. 26% of eyes had severe to profound visual impairment i.e. were legally blind, at the final visit. Conclusion The results of 21 black African IIH patients reported in this study were similar to some other studies with regards to demographics, clinical features and clinical and visual outcomes. An association between IIH and oral contraceptives, steroids and hypertension could not be established. Although symptoms resolved in most patients, a significant number of patients still had papilloedema and visual field loss following treatment. Despite treatment, a quarter of the patients were legally blind at the final visit, indicating that this condition is not benign.

A thesis submitted to the Faculty of Medicine, University of the Witwatersrand, Johannesburg, in fulfilment of the requirements for the degree of Doctor of Science (Medicine). / The publications forming this submission cover two broad fields. A series of papers deal with experimental hypertension ; possible roles for angiotensin and prostanoid substances in the pathogenesis of hypertension were investigated. The results indicated that the capacity of kidney to inactivate angiotensin II could be quite profoundly altered by inducing hypertension using the one and two-clip Goldblatt methods or by altering the sodium chloride content of the diet. / IT2018

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.

M.Sc. (Physiotherapy), Faculty of Health Sciences, University of the Witwatersrand, 2011 / Background Poor adherence to lifestyle interventions and medication-taking poses a problem universally. However, there are interventions to help patients adhere to treatment regimens and in turn, lower the risk of cardiovascular disease by decreasing blood pressure. These interventions need to be investigated further. Change in risk factors as a result of a lifestyle modification adherence tool in patients with chronic hypertension is not clear and will be further investigated in this study. Aim To determine the effect of a lifestyle modification adherence tool in patients with chronic hypertension and compare this with usual management. Objectives 1. To compare the changes in: · Blood pressure · Waist-hip ratio · Weight and body mass index · Blood glucose, cholesterol, triglycerides, HDL and LDL levels · Exercise Capacity between two experimental and one control group at baseline and after a six month intervention using a lifestyle modification tool 2. To determine the sustainability of the intervention three months after the intervention is concluded. Design The study design was a quantitative, longitudinal randomized control trial consisting of two experimental and one control group. Method Ninety subjects at the hypertension clinic at Helen Joseph Hospital were sampled consecutively and then randomized using computer generated randomization and concealed allocation. The study consisted of three groups, two experimental and one control group. All three groups underwent the usual treatment in the Hypertension Clinic. Experimental group one (EG1) received the Lifestyle Modification Adherence Tool (LMAT) as well as a once-a-month telephone call from the research assistant. Experimental group two (EG2) received only a once-a-month telephone call from the research assistant. The control group (CG) received the standard treatment at the clinic. The significance of the study was set at p=0.05. A Students t-test (independent) was used to compare variables between groups at baseline. The Pearsons Chi Square test was used to compare and analyze non parametric data at baseline. Change in blood pressure, waist-hip ratio, weight and body mass index, glucose levels and exercise capacity between control and intervention groups was established using an ANCOVA. Pairwise t-tests were used to compare p-values between groups one and two; one and three and; two and three. Results No reductions in weight and body mass index (BMI) were observed. Significant differences in EG1 for waist/hip ratios were noted compared with the EG2 (p=0.04) and CG (p=0.04) between month 0 and month 6. Blood pressure reductions were greater in EG1 compared with EG2 and the CG at six months but greater drops in blood pressure were noted in EG2 compared with EG1 and the CG between six and nine months. However, these differences were not significant. Significant reductions were observed in blood glucose levels in the EG1 compared with EG2 group between month 6 and month 9 (p=0.05). There were also significant reductions in the EG2 in triglycerides and low density lipoprotein (LDL) between month 0 and month 6 compared with the CG (p= 0.04 and p= 0.03 consecutively) and significant LDL reductions in both EG1 and EG2 between month 6 and month 9 compared with the CG (p= 0.02 for both comparisons). Walking distances improved minimally in both EG1 and EG2 but these changes were not significant. Conclusion Although not all results were significant, diary and telephone interventions and telephone only intervention to improve adherence did show a positive trend towards improvements in risk factors of patients with chronic hypertension.

Thesis advisor: Catherine Y. Read / Background and Significance: The metabolic syndrome is a heterogeneous disorder leading to increased morbidity and mortality. Components of the metabolic syndrome are known to be inherited, however efforts to identify genomic markers in humans have been unsuccessful and a candidate-gene/intermediate phenotype approach may be useful. Evidence supports a relationship between altered metabolic function and three candidate genes, caveolin-1 (CAV1), peroxisome proliferator receptor-activated gamma, and angiotensinogen (AGT). These genes may serve as markers for the co-aggregation of insulin resistance and hypertension. Research Question: To examine whether single nucleotide polymorphisms (SNPs) in the CAV1, PPARg and AGT genes are associated with the co-aggregation of insulin resistance and hypertension. Methods: Three gene association studies were conducted in a Caucasian hypertensive cohort (HyperPATH). The homeostasis assessment model (HOMA-IR), hyperinsulinemic euglycemic clamp, and salt sensitive blood pressure were determined in each subject. Statistical analyses were conducted using a general linear model accounting for relatedness and adjusting for the following covariates: age, gender, body mass index, study site. Replication was assessed in a hypertensive Mexican-American cohort (HTN-IR) for the CAV1 gene and a hypertensive African American cohort (HyperPATH) for the PPARg gene. Results: SNPs of the CAV1 gene were significantly associated with insulin resistance in Caucasians from HyperPATH. These results were replicated in the HTN-IR cohort. A SNP of the PPARg gene was associated with salt sensitive blood pressure and increased plasma renin levels in Caucasians and African Americans from HyperPATH. SNPs of the AGT gene were associated with insulin sensitivity in Caucasians from HyperPATH. Conclusion: CAV1 and AGT are genomic markers for the co-aggregation of insulin resistance and hypertension. The PPARg gene is a potential genomic marker for vascular dysfunction in hypertension. Clinical Perspective: Genomic markers for insulin resistance exist in human populations with hypertension. These markers explain the inter-individual variability of insulin resistance and hypertension and help identify potential underlying mechanisms. Use of these bio-markers in clinical practice may improve individualized prevention and treatment strategies, decreasing the incidence of and improving outcomes for this chronic disease. Promoting health through individualized care makes the incorporation of genomic markers into nursing practice essential. / Thesis (PhD) — Boston College, 2010. / Submitted to: Boston College. Connell School of Nursing. / Discipline: Nursing.

Hypertension (HTN) is highly prevalent globally among low- and middle-income countries (LMICs). By 2020, cardiovascular disease (CVD) deaths related to HTN in LMICs are projected to increase by 75%. HTN control in LMICs is hindered by an acute shortage of physicians, limited diagnostic medical equipment, and a dearth of disease management resources. Despite the increasing prevalence of HTN in LMICs, scalable, evidence-based interventions to reduce morbidity and mortality attributed to HTN are rarely applied in these settings. The TAsk-Shifting Strategy for Hypertension (TASSH), a 5-year cluster-randomized controlled trial that has been implemented in community health centers in the Ashanti region of Ghana, is an evidence-based example of a scalable intervention strategy for LMICs that can effectively control HTN. The aims of this study were to: (a) conduct a systematic review of interventions for HTN control implemented in LMICs and assess the effect on blood pressure control as demonstrated in RCTs that stated “scale-up”; (b) identify the WHO/ExpandNet scale-up components (i.e., Inputs, Outputs, Outcomes, Impact, Cost effectiveness, Equity, Embedded within current health organization policy, Monitoring and evaluation, Sustainability); and (c) investigate the community health nurse stakeholders’ (n = 27) perceptions of the evidence-based TASSH cluster-randomized controlled trial in Ghana. Twenty-nine randomized-controlled trials describing potentially scalable HTN control intervention strategies and WHO/ExpandNet components were identified. Studies reported clinically significant differences in blood pressure, with 16 studies reporting statistically significant mean differences in BP (p < 0.05). Multicomponent interventions, including drug therapy and health education, provided the most benefit to participants. However, there was limited reporting on translation into existing institutional policy, cost effectiveness, stakeholder engagement, and sustainability. Patient goal setting, leadership engagement, and availability of resources, all of which were mentioned by TASSH nurses as important for successful implementation and eventual TASSH scale-up, emerged as major themes. LMICs need context-specific metrics and indicators to effectively evaluate and standardize the reporting of scale-up components and processes. In addition, infrastructure development, including capacity building at the individual, institutional, and systems levels, as well as stakeholder engagement (i.e., leadership), are necessary to address HTN-related morbidity and mortality and other diseases.

INTRODUCTION Preeclampsia, a hypertensive disorder of pregnancy, affects 3% to 7% of women throughout the world. Preeclampsia is a leading cause of maternal and infant mortality worldwide, occurring primarily in nulliparous women. Despite extensive research over the past decade, the underlying pathophysiological mechanisms of the disease are largely unknown. A recent hypothesis has suggested that when a pregnancy is complicated by preeclampsia, it is the result of an inability of the maternal cardiovascular system to fully adapt to the physiologic challenge of pregnancy. This may result when there is an underlying and predisposing prepregnancy maternal cardiovascular state that leads to the pathophysiologic consequences of preeclampsia when pregnancy is superimposed. Despite evidence for familial predisposition and presumed multifactorial genetic inheritance, preeclampsia generally occurs in first pregnancies and does not recur when the interpregnancy interval is short. One explanation for these observations is that pregnancy itself modifies the maternal cardiovascular system in ways that persist postpartum and reduce the risk for preeclampsia recurrence, at least for a limited period of time. It has been demonstrated that the maternal cardiovascular system is remodeled during pregnancy, and these changes extend postpartum. The long lasting reduction in mean arterial pressure postpartum that pregnancy induces, and the cardiovascular remodeling that accounts for this, may allow for easier adaptation to volume expansion in subsequent pregnancies, even when the first pregnancy was complicated by preeclampsia. As the maternal cardiovascular system returns, over time, to the baseline condition, this protective effect diminishes. With this knowledge, we hypothesize that the length of time between pregnancies is negatively correlated to the likelihood of recurrence of preeclampsia, and more narrowly that the length of time between pregnancies is inversely associated with mean arterial pressure differences comparing pregnancies across all trimesters. METHODS This study was a retrospective chart review of existing medical records. We reviewed medical records of women who had been diagnosed with preeclampsia at Fletcher Allen Health Care, during their first advanced pregnancy between 1995 and 2014, who went on to have a subsequent pregnancy within that time period. We aimed to identify factors that could affect the blood pressure and risk of preeclampsia in women who were previously diagnosed, including previous medical history and demographic variables. We collected blood pressures from each pregnancy, across each trimester, marking the recurrence of preeclampsia and other complications. Mean antepartum mean arterial blood pressure, pulse pressure, and systolic and diastolic blood pressures were calculated and compared between pregnancies examining differences as a function of interpregnancy interval. RESULTS One hundred and seventy two subjects were identified for review. Overall, there was evidence of a significant association of interpregnancy interval (IPI) and the difference in mean arterial pressure (MAP) between pregnancies (p=0.04). The mean MAP of pregnancy decreased significantly between first and second pregnancies when the interpregnancy interval was <24 months (p=0.0018) and 24-48 months (p=0.0003), but the change was non-significant at interpregnancy intervals of >48 months (p=0.55). The mean MAP during the third trimester, specifically, decreased significantly between first and second pregnancies across all subject groups (IPI <24 months: p<0.0001; IPI 24-48 months: p<0.0001; IPI >48 months: p=0.03). Preeclampsia recurred in 39 of the second pregnancies. The recurrence rate of preeclampsia did not vary significantly with interpregnancy interval (p=0.21). DISCUSSION/CONCLUSIONS The interval between preeclamptic pregnancies and subsequent pregnancies has an influence on the MAP of the second pregnancy. There is good evidence of a temporal influence, in that the shorter interpregnancy intervals resulted in a greater reduction in MAP when compared to the longer interpregnancy interval. We believe that with additional research on interpregnancy intervals >48 months, there could be more a conclusive association identified between the rate of recurrence of preeclampsia and the length of interpregnancy interval.

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.