Cardiovascular disease (CVD) is highly prevalent in chronic kidney disease (CKD) patients. Whilst this can in part be explained by the high incidence of traditional CVD risk factors such as hypertension and diabetes evident in CKD patients, recent focus has been on non-traditional risk factors and their role in CVD progression. These include endothelial dysfunction, arterial stiffness, inflammation and oxidative stress. The potent vasoconstrictor endothelin-1 (ET-1) has been implicated in the pathogenesis of CKD and the CVD associated with it. Further understanding of the mechanisms by which it contributes to CKD and CVD pathogenesis, specifically its interactions with non-traditional risk factors are still required. Additionally, the potential applications of ET antagonists in renal disease have not been fully explored. This thesis aims to investigate the role of ET-1 in the development of renal disease and the associated inflammation, hypertension and vascular dysfunction through a series of in vitro, in vivo and clinical studies. I have demonstrated using in vitro techniques that murine macrophages (Mϕ) express both endothelin A (ETA) and endothelin B (ETB) receptors but that ET-1 does not elicit either a classical pro-inflammatory or alternative anti-inflammatory phenotype in Mϕ. I was however, able to show that M display chemokinesis towards ET-1 and M ETB receptors provide a novel clearance mechanism for ET-1 through receptor mediated dynamin-dependent endocytosis In an in vivo study I investigated whether ET-1 mediates the progressive renal injury after renal ischaemia reperfusion injury (IRI) that leads to the development of CKD. I demonstrated that endothelin A receptor antagonism provided long term beneficial effects reducing blood pressure and preventing progressive kidney injury, inflammation, and the development of fibrosis resulting from an episode of acute kidney injury (AKI). Similar benefits were observed with calcium channel blockade, suggesting hypertension may mediate some of the long term effects of renal IRI and anti-hypertensive treatments could prevent the development of CKD after AKI. Finally, in a clinical study I showed for the first time that CKD patients lack the diurnal variation in arterial stiffness that is seen in matched subjects without CKD. Alteration in the circadian variation of the ET-1 system may contribute to this. In summary, my studies have furthered our understanding of the role of ET-1 in CKD progression and the cardiovascular risk associated with it. Mϕ were shown to express both ET receptors and a novel mechanism of ET-1 clearance was observed in Mϕ. Using an in vivo model of AKI I was able to identify ETA receptor antagonism as a novel therapeutic agent in preventing the development of CKD caused by AKI where data are limited. Finally, alterations in the circadian rhythm of the cardiovascular system is emerging as an important factor in disease pathogenesis. Here the diurnal variation in arterial stiffness was described for the first time in a group of CKD patients and matched controls.

Background: The prevalence of overweight, obesity and obesity-related disease, mainly cardiovascular disease (CVD), is increasing in both developed and developing countries. Ethnic differences have been reported in the prevalence of overweight, obesity and CVD. However, measures used to define overweight and obesity, and identify increased risk of CVD were developed and validated in predominately Caucasian populations in developed countries. Consequently, these measures may not accurately define disease risk in all population groups. Therefore the specific aims of this programme of study were: 1. To establish the relationship between adiposity and cardiovascular risk factors in different ethnic groups. 2. To identify field measures of adiposity, relating to cardiovascular risk in different ethnic groups. 3. To compare the relationship of adiposity and cardiovascular risk factors in a single ethnic group, that of a rural and an urban population in Zimbabwe. 4. To identify risk factors for CVD related to adiposity in a population of African origin. Study design: Three empirical studies were undertaken. In study one, 312 adult subjects from three ethnic groups (Afro-Caribbean (n=106), Caucasian (n=165) and South Asian (n=41)) were recruited from a University. Twenty-six (26) of each group were individually matched for age (±3 years) gender and BMI (±2 kg/m2) to allow for comparability. Measures of body composition included height, weight, waist and hip circumferences, skinfold thickness measures, body density and percentagebody fat. In study two, 81 subjects from two ethnic groups (Afro-Caribbean (n=39) and Caucasian (n=42)) were recruited and tested. They were matched for age, gender and BMI using the same criteria as study one. In addition to the body composition measures taken in study one, random non-fasting blood glucose, total cholesterol, triglycerides and blood pressure were taken. In study three, 55 men and 108 women from rural Zimbabwe, 8 men and 17 women from an urban low-density suburb in Harare Zimbabwe, and 28 male and 16 female students from the University of Zimbabwe were recruited and tested. In addition to all measures of body composition in studies one and metabolic analysis in study two, participants’ dietary intake was assessed by food frequency questionnaire and 24hour recall and physical activity was assessed by a physical activity questionnaire. Main findings: • The relationship between BMI and %BF was not the same in all ethnic groups. (aim 1) • There were ethnic differences in the cardiovascular risk predictors between Afro-Caribbean and Caucasian men and women. (aim 1) • It is not recommended that BIA is used as a substitute for TBW estimation in multi-compartment models. (aim 2) • In three groups of Zimbabweans from urban, rural and university locations, a pattern emerged. Amongst women, urban women were at greatest risk, reporting highest values for all variables, followed by rural then university women. Amongst men, urban men were at highest risk, however there were few differences between rural and university men. (aim 3). • Finally, increased WC and dyslipidemia are associated with increasing BMI in populations of African origin. (aim 4) Conclusions: The relationships between overweight, obesity and risk of obesity-related disease differ between different ethnic groups. Moreover, in the groups from Zimbabwe, differences in obesity-related risk were associated with being female and living in urban areas. Therefore, application of universal measures for defining obesity and related diseases may not be applicable to all ethnic groups.

Arterial stiffness is one of the major risk factors and markers of cardiovascular disease (CVD). An increase in the arterial stiffness is influenced by various factors such as age, lifestyle, genetics and the presence of other cardiovascular risks such as obesity and diabetes. Arterial stiffness is a consistent thread in this thesis. This thesis investigates the effects of exercise-based management programmes for CVD and risk factors with a focus on carotid-radial applanation tonometry which is a specific non-invasive technique for measuring arterial stiffness. Erectile dysfunction is a marker of CVD and is associated with endothelial dysfunction that leads to arterial stiffness. The effects of centrebased, supervised and exercise-based cardiac rehabilitation (CR) programmes were studied on the changes in arterial stiffness, erectile dysfunction and quality of life of patients with CVD. Despite the effectiveness of CR programmes, there is poor attendance at these programmes and unsupervised home-based, IT (information technology)-supported programmes could improve patient participation and cost effectiveness. Moreover, earlier identification of risks and appropriate management can reduce the incidence of CVD. There are no such programmes for early stages of CVD in practice, especially in developing countries such as India. A 12-week, IT-supported home-based exercise programme in India, for patients with metabolic syndrome was developed and studied. In general, arterial stiffness was improved in both centre-based and home-based exercise programmes. There were acute increases in arterial stiffness following exercise in healthy Caucasians and South Asians as well as people with metabolic syndrome. Carotid-radial pulse wave analysis could be a simple and reliable prognostic tool in exercise based rehabilitation programmes.

Vascular calcification is strongly correlated with the clinical manifestations of atherosclerosis, heart attacks and strokes. The calcification process resembles bone formation and involves the osteogenic trans-differentiation of smooth muscles cells within the arterial wall. Cannabinoid receptors are known to modulate bone formation and are present in atherosclerotic vessels, suggesting they may also play a role in modulating calcification. Therefore, we evaluated the effects of cannabinoids on the expression of osteogenic proteins by vascular smooth muscle cells undergoing calcification.

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Background: Diabetes is the sixth leading cause of death in the United States (U.S), and a major risk factor for cardiovascular disease (CVD). The prevalence of diabetes in central Appalachian region is higher than the rest of the nation (14.4% versus 9.0%, respectively). Objectives: Examine the association between multiple risk factors for CVD and diabetes in asymptomatic adults in central Appalachia. Methods: Between January 2012 and July 2016, 3,000 community-dwelling asymptomatic individuals from central Appalachia participated in screening for sub-clinical atherosclerosis. Participants were asked to report their diabetes status (yes/no). In addition, data on coronary artery calcium (CAC), a marker for sub-clinical coronary atherosclerosis, in quartiles (0, 1-99, 100-399, ≥400), obesity (body mass index ≥30 kg/m2), hypercholesterolemia (yes/no), hypertension (yes/no), current smoking (yes/no), sedentary lifestyle (yes/no), and family history of coronary artery disease (CAD) (yes/no), were collected. Multivariable logistic regression analyses were conducted to assess association between CVD risk factors and diabetes. Results: Of the 3,000 participants, 2,509 subjects (mean age: 58.3 years; SD = 9.8 years) had complete data on variables of interest. Approximately, 14% of the study population reported having type 2 diabetes. Among subjects with diabetes, 58% had a CAC score ≥1, 22% were obese, 17% had hypercholesterolemia, 20% had hypertension, 16% were current smokers, 17% had a sedentary lifestyle, and 15% had a family history of CAD. After adjusting for sex and age, having a CAC score of 1-99, 100-399, and ≥400 increased the odds of having diabetes (Odds ratio (OR): 1.4, 95% Confidence interval (CI) = 1.02-1.9; OR: 2.0, 95% CI = 1.4-2.8; OR: 3.1, 95% CI = 2.1-4.7, respectively) in a linear fashion. Being obese (OR: 3.2; 95% CI = 2.5-4.0), having hypercholesterolemia (OR: 1.8; 95% CI=1.4-2.4), being hypertensive (OR: 3.0; 95% CI= 2.3-3.8), being a smoker (OR: 1.5; 95% CI = 1.1-2.1), and being sedentary (OR: 1.6; 95% CI = 1.3-2.0) were significantly associated with diabetes. Having three (OR: 3.0; 95% CI=1.3-6.6), four (OR: 4.4; 95% CI=2.0-9.7), five (OR: 7.0; 95% CI=3.1-16.1) or six (OR: 9.9; 95% CI= 3.5-27.7) CVD risk factors significantly increased the odds of diabetes. Subjects with any of the seven risk factors under study were 1.7 times (95% CI= 1.5-1.9) more likely to have diabetes. Conclusion. Odds of type 2 diabetes increase with higher number of risk factors for CVD. Results support the use of multifaceted CVD and diabetes prevention programs to lower the incidence of type 2 diabetes.

A research report from the Centers for Disease Control and Prevention (CDC) indicated that more than 50% of people with diabetes mellitus (DM) in the United States (U.S.) also have arthritis. The diabetes population is disproportionately affected by arthritis, but there has been limited and inconsistent research to confirm the association between type 2 diabetes mellitus (T2DM) and rheumatoid arthritis (RA). The current study aimed to identify an association between T2DM and RA for noninstitutionalized U.S. adults between 1999 and 2012 using a nationally representative sample from the National Health and Nutrition Examination Survey (NHANES) database (n =31,488 ). A quantitative, cross-sectional investigation was conducted to determine if patients with T2DM had an increased prevalence of RA. The current study also sought to identify characteristics that could affect the association between both groups and the prevalence of cardiovascular disease (CVD) in this population. Prevalence and adjusted odds ratios (OR) using logistic regression were calculated. The results show evidence of a strong association between T2DM and concomitant RA. Prevalence of RA was significantly higher in participants with T2DM compare to those without T2DM. Important factors in this association were gender, ethnicity, education, disability, and work functioning. The prevalence of CVD and adjusted OR of association were doubled in participants with T2DM and RA when compared to participants who had just one of the conditions; the OR of association was quadrupled when compared to those without this comorbidity. This study may provide patients and health care providers with a better understanding of the need for management of both conditions in a interdisciplinary manner

The elderly population in the United States is growing rapidly, presenting increasing challenges in health care provision. One of the most salient and complex issues facing the elderly is cognitive impairment. This condition often leads to dementia and has a significant quality of life and financial impact. One of the most common and preventable causes of cognitive decline is heart disease, specifically atherosclerotic vascular disease (AVD). This condition is related to myriad health risk factors and conditions, including sleep disorders. The current study examined 51 adults between the ages of 55 and 88 with a diagnosis of AVD. Participants were divided into sleep disordered (N = 20) and non sleep disordered (N =31) groups and compared in terms of fatigue, performance on neuropsychological testing, and a marker of inflammatory pathology. Participants with sleep disorders and AVD reported significantly greater levels of daytime fatigue and performed significantly more poorly on objective cognitive testing than those with AVD alone. Implications for the relationship of disordered sleep, AVD, and cognition as well as future research directions are discussed.

Regular aerobic exercise may reduce cardiovascular disease (CVD) risk in part by lowering the concentration of inflammatory markers such as C-reactive protein (CRP). While studies in diseased populations have shown significant decreases in CRP concentrations with regular aerobic training, little has been conclusively determined regarding the effects of aerobic training on CRP concentrations in apparently healthy, untrained populations who may not be adequately screened for CVD risk by traditional methods. PURPOSE: To examine the effects of a 17-wk half marathon training program (TP) on CRP concentrations, aerobic fitness, and body composition in apparently healthy, untrained men. METHODS: Twenty men (29.3 ± 1.0 yr, 37.0 ± 1.6 mL•kg-1•min-1 VO2max, 29.1 ± 1.8% body fat) registered as training subjects (TRN) in a 17-wk half marathon TP. An additional 22 men (27.8 ± 1.4 yr, 38.8 ± 1.0 mL•kg-1•min-1 VO2max, 26.8 ± 1.4% BF) served as controls (CON). Fasting blood samples were taken at four time points over the TP and were analyzed for CRP and interleukin-6 (IL-6) concentrations. Aerobic capacity (VO2max) and body fat (BF%) were measured before and after the TP. RESULTS: No significant changes in CRP (P=0.69) or IL-6 concentrations (P=0.73) were seen in TRN as a result of the TP despite significant improvements in VO2max (42.2 ± 1.9 ml•kg-1•min-1, P<0.0001), resting heart rate (P =0.004), BF% (P =0.03) and BMI (P =0.05). No significant changes in CRP, aerobic fitness, BMI or BF% were detected in CON over time. CONCLUSION: Moderate, long-term aerobic training does not appear to affect CRP concentrations in apparently healthy, untrained men despite significant improvements in BW, BF%, BMI, and VO2max.

The purpose of this research was to examine and describe the relationships among health status, marital status, income level, education level, age, and body mass index (BMI) with the added influence of spirituality on the health promotion behaviors of African American women, living in South Florida. The sample consisted of 137 women, 18 to 64 years of age, who were born in the United States and whose parents were born in the United States. Each participant completed a demographic questionnaire, the Health-Promoting Lifestyle Profile II (HPLP II), the Short Form-36 Health survey (SF-36), and the Spiritual Well-Being Scale (SWBS). Descriptive and inferential statistics with an alpha level of .05 were used for data analysis. Statistically significant findings were (1) a positive relationship between health promotion behaviors and formal education, (2) a positive relationship between health promotion behaviors and spirituality (existential well-being), and (3) a negative relationship between health promotion behaviors and number of children. In the regression model, the five sets of variables together accounted for 25.5% of the variance in overall health promotion behaviors of African American women F (15, 121) = 2.768, p < .01. The health promotion behaviors of African American women were not significantly affected by health status, marital status or BMI. Of the five demographic variables entered in the model, only number of children and education made statistically significant, unique contributions to health promotion behaviors. A sense of life satisfaction and purpose (existential well-being) made an additional, statistically significant, unique contribution to health promotion behaviors among African American women. The unique contribution of religious well-being was trivial. Therefore, formal education, number of children, and spirituality (existential well-being) may be used as predictors of health promotion behaviors among African American women, based on the results of this study. Culturally appropriate and relevant interventions used to encourage and educate African American women to increase physical activity, and decrease caloric intake are critical to mitigate the high rate of morbidity and mortality that African American women experience from CVD.