Background: Rheumatoid arthritis (RA) is an inflammatory disease associated with an increased risk of cardiovascular morbidity and mortality. Methotrexate is a widely used RA medication that has encouraging results for being protective from RA cardiovascular related complications. In a published meta-analysis, MTX showed a 21% reduction in cardiovascular mortality; however, this meta-analysis had multiple limitations. Arterial stiffness is considered to be one of RA's extra-articular manifestations. As a common medication, could MTX have a beneficial effect on traditional cardiovascular risk factors and arterial stiffness parameters? Aims: The aim of this thesis is to assess the effect of MTX on cardiovascular morbidity and mortality using meta-analysis and a cross sectional and longitudinal study to determine whether MTX therapy is associated with reduced blood pressure, AS parameters (measured by pulse wave velocity (PWV), augmentation index (AIX)) and other traditional cardiovascular risk factors (glucose, lipids) in rheumatoid arthritis patients in Saudi Arabia. Methods: Meta-analysis of cohort study design was conducted using combined reporting guidelines. Studies were selected using a systematic search in five databases. Meta-analysis of the effect estimate of the cohort study design was done using a fixed effect model. Another part of the thesis is a cross sectional and longitudinal study of RA patients attending the rheumatology clinic at the university hospital in Saudi Arabia that were classified into three groups: 'current-MTX', which were patients that took MTX for at least three months; 'no-MTX', which were patients that were not on MTX for at least one year; and 'new-MTX', which were patients that were due to commence MTX directly after recruitment. Arterial stiffness and central 2 blood pressure parameters were assessed in RA patients using a validated non-invasive Mobil-O-Graph device. Other cardiovascular and non-cardiovascular parameters were also assessed during patient recruitment from patient interviews, medical records and the laboratory database. Patients were followed-up with two times. Linear regression analysis was performed; a mixed model for repeated measures was done to evaluate the effect of time on differences in blood pressure and arterial stiffness between groups. Results: Nine studies were included in the meta-analysis, and MTX showed a 46% reduction in cardiovascular events. Non-significant heterogeneity was documented between studies. A total of 353 patients (mean age 49 years, female 89%, median RA duration 10 years) were recruited at baseline (March 2013 to January 2014); with 117 reassessed over 3-6 months of follow-up. Augmentation index of the 'current-MTX' group was reduced compared to the 'no-MTX' group by 1.1 (95% CI -4.7 to 2.6) %; and systolic blood pressure was increased by 2.5 (95% CI -2.3 to 7.4) mmHg in 'current-MTX', but results were not statistically significant. During follow-up, no difference was found between treatment groups or within each individual group in the longitudinal analysis. Conclusion: Methotrexate is associated with reduced cardiovascular events on meta-analysis of cohort studies. In the cross sectional setting and longitudinal analysis, methotrexate did not prove to be beneficial in reducing arterial stiffness and blood pressure parameters and other cardiovascular risk factors in rheumatoid arthritis patients in Saudi Arabia.

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No description available.

Background: Obstructive Sleep Apnea (OSA) is a chronic breathing disorder that is estimated to affect 20% of the US adult population. Intermittent hypoxia and sleep fragmentation caused by OSA likely affects cardiometabolic function. Individuals with OSA might be at risk of developing hypertension and type 2 diabetes (T2DM), with a dose-response relationship related to OSA severity. The objective of this study was to estimate the association between severity of OSA at diagnosis with 1) incidence of hypertension incidence of hypertension and 2) incidence of T2DM. Methods: We conducted a retrospective cohort study of Kaiser Permanente members diagnosed with OSA during 2000-2005. Adults without baseline hypertension or T2DM were eligible. Patients were excluded if hypertension or T2DM was diagnosed within one year prior to OSA diagnosis, and right censored at the end of follow-up or at the time Kaiser Permanente membership ended. Kaplan-Meier curves and Cox Proportional Hazard models were used to estimate the association between OSA severity and incident hypertension and incident diabetes. Results: Overall 719 patients were diagnosed with OSA during the study periods; 614 were included as those at risk of developing either hypertension (N=265) or T2DM (N=489). Overall, 261 had severe OSA at diagnosis. Those with severe OSA were more likely to be middle aged, overweight, and have prevalent hypertension or T2DM. Among those without prevalent hypertension at OSA diagnosis, 47.4% (126/266) were subsequently diagnosed with hypertension. Among those without prevalent T2DM at OSA diagnosis, 16.3% (80/491) were subsequently diagnosed with T2DM. After adjusting for BMI and prevalent T2DM, the hazard rate of incident hypertension among patients with severe OSA was 1.35 (95%CI: 0.88-2.06) compared to the rate among patients with mild OSA. The hazard rate of incident T2DM among patients with severe OSA was 1.49 (95%CI: 0.83-2.67) compared to the rate among patients with mild OSA after adjusting for BMI and prevalent hypertension. Discussion: We found high incidence rates of hypertension and T2DM among adults diagnosed with OSA. Severe OSA at diagnosis was associated with increased risk of either incident hypertension or T2DM, but not significantly (for p≤0.05).

published_or_final_version / Physiology / Doctoral / Doctor of Philosophy

The purpose of this research was to determine whether adipocytes express ACE2 and its role in obesity-associated hypertension with diet-induced obesity. To determine if ACE2 was expressed in adipose tissue and its regulation in the setting of diet-induced obesity, we fed male mice either a low fat (LF) or high fat (HF) diet acutely (1 week) or chronically ( 4 months). We demonstrated that ACE2 was regulated specifically in adipose tissue with consumption of a HF diet. However, with chronic HF feeding adipose ACE2 was dysregulated resulting in activation of the systemic RAS and increased blood pressure. To determine the role of ACE2 in obesity-associated hypertension, we used ACE2 deficient male and female mice. Wild type and ACE2 deficient mice were chronically fed either a LF or HF diet. Metabolic parameters were measured during the entire course of the study and blood pressure was measured by telemetry at the end of the study. Results from these studies demonstrate that HF diet promotes obesity-associated hypertension in male mice which is further augmented with ACE2 deficiency. Further, ACE2 deficiency resulted in marked glucose intolerance suggesting that stimulation of ACE2 may blunt the progression of obesity-associated diabetes. In contrast to the males, females are protected against obesity-associated hypertension. However, this protection in the females is lost with ovariectomy and ACE2 deficiency. These results suggest that female sex hormones protect the females against obesity-associated hypertension by regulating ACE2. To define mechanisms for HF diet-induced regulation of ACE2 in adipose tissue we examined various fatty acids for their ability to regulate ACE2 mRNA abundance in 3T3-L1 adipocytes. We revealed that omega-3 fatty acids, known regulators of PPARγ, increased ACE2 mRNA abundance in adipocytes. Therefore, we examined in vitro and in vivo regulation of ACE2 in 3T3-L1 cells and adipose tissue by PPARγ receptor ligands (TZDs). Results demonstrate regulatory effects of PPARγ to promote ACE2 gene transcription. These effects were associated with changes in glucose tolerance. Taken together, these results demonstrate that adipose ACE2 plays a protective role against obesity-associated hypertension in male and female mice and is regulated by natural and synthetic ligands of PPARγ.

The study was conducted in two phases. Phase I consisted of generating models of risk reduction behaviors in order to implement and test risk reduction interventions for Phase II. The purposes of Phase I were: (a) to identify among a group of African-Americans individual and group risk factors for hypertension, and to identify demographic and psychosocial variables most predictive of risk reduction behaviors for hypertension, (b) to design and test a model that combines important demographic and psychosocial determinants of risk reduction behaviors, and (c) to generate data based models of the predictors of each risk reduction behavior for hypertension in the group of African-Americans. The conceptual model for the study was developed by combining variables from the Health Belief Model--susceptibility, severity, and barriers with variables from social learning theory-health locus of control and self-efficacy. The focus of Phase I was to test the model to determine the interactions among the variables, because the assumptions of the underlying theories suggest multiplicative rather than linear relationships. One hundred forty-three subjects completed Phase I. The demographic variables age, gender, and education entered the model as direct effects and strong moderators. Education was a direct effect for stress reduction and moderated the effect of risk severity in diet fat. Age as a direct effect explained 19 percent of the variance in diet sodium intake and 21 percent of the variance in diet fat as a direct effect and moderating effect of risk severity. Twenty-seven percent of the variance in alcohol use was explained by age (B = -.24) difficulty (B =.26), and risk health value moderated by age (B = -.27). Sixty-three percent of the variance in smoking behaviors was explained by the direct effects of age (B = -.20), gender (B = -12) and difficulty (B =.25), and by the interaction of age and difficulty (B =.52). In Phase II, interventions were developed that used either motivational or educational skills strategies such as monetary incentives, screening, risk assessment, health education, dietary analysis, and self-monitoring. Twenty-eight subjects participated in the pilot test of Phase II. Participants were most interested in modifying their diet fat intake and increasing stress reduction. The findings that each risk reduction behavior was predicted by different variables and/or different interaction patterns of the same variables supports further study of each risk reduction behavior rather than looking at risk reduction behavior as a conglomerate or as a summed health-promotive behavior. The study also supported the underlying theoretical assumptions of the Health Belief Model, and Social Learning Theory that the relationships between the variables is multiplicative, as moderating effects were found, but no mediating effects were supported.

A growing literature suggests that training in relaxation or meditation results in significant reductions in blood pressure in hypertensive patients. The present study was designed to assess the efficacy of a combination relaxation and meditation training program structured by the author and previously used in treatment of a broad spectrum of anxiety-related clinical problems of either a medical (somatic) or a psychological (cognitive and emotional) nature. The 20 subjects were a heterogeneous clinical group of veterans with mild hypertension who were seen at the Tucson Veterans Administration Medical Center. Volunteers were randomly assigned to either (I) an education/cognition group, (II) a three-treatment relaxation/meditation group, or (III) a six-treatment relaxation/meditation group. Blood pressure, anxiety, and stress were measured at regular intervals during training and follow up. All groups were trained over a six-week period. Both relaxation/meditation groups were taught the same skills; only the schedules for training were varied. The educational group, conceived as a control for therapist attention, was, in fact, a cognitive treatment group. Statistically significant reductions in both systolic and diastolic blood pressure were found over time in all groups, while no difference in blood pressure reductions was found among the groups. Anxiety scores increased over time, and no correlation was found between subjective anxiety and objective blood pressure measures. Means of both systolic and diastolic blood pressure were lower at times when subjects reported no stress. Results of this study tend to support those of previous studies, finding statistically significant reductions in systolic and diastolic blood pressure over time in two groups of hypertensive subjects trained in relaxation and meditation techniques. No difference was found, moreover, between these groups and an education/cognition group, suggesting that group techniques, in either significant lowering of blood pressure. This finding lends support to a multiprocess theory which suggests that all treatments have multiple effects.

This study examined the difference among 3 patient education intervention strategies and compliance in the hypertensive elderly. The strategies were verbal instructions, written instructions and both verbal and written instructions. An ex post facto descriptive design was implemented based on a Cognitive Information Processing Theory of Learning. Forty subjects were recruited and interviewed. Data analysis revealed that compliance did not differ significantly with the type of educational strategy.

No description available.