Data were collected from the initial graded exercise tests of 116 cardiac rehabilitation patients. Subjects were grouped according to their blood pressure response to exercise. Blood pressure groupings were typical systolic and typical diastolic (S_TD_T); typical systolic and atypical diastolic ( S_TD_AT); atypical systolic and typical diastolic (S_ATD_T); and both atypical systolic and diastolic blood pressure responses to exercise (S_ATD_AT). Groups were investigated for incidence of atypical responses (decrease, no increase, or excessive increase in systolic pressure and/or excessive increase or high diastolic pressure) and differences in physical characteristics, CVD status, predisposing CHD variables, medications prescribed, peak exercise cardiovascular responses and indicators of myocardial dysfunction. Results revealed atypical blood pressure responses in 65.5% of the subjects. No change in systolic pressure between the last two measured blood pressures was the most frequent atypical response exhibited. The S_ATD_AT pattern group was suggested to be at a higher health risk than the other groups based upon the tendency for higher percentages of subjects in this group exhibiting a history of myocardial infarction (80%), CABG (20%), angina ( 40%) and hypertension (47%). A high percentage of these subjects had been prescribed antihypertensive and antiarrhythmic medications, had "borderline" resting hypertension (X = 135.2/86.3 mmHg) and smoked (61.5%). Peak exercise data revealed a higher heart rate, higher systolic and diastolic pressures, higher RPE, more marked decreases in ECG changes and more supraventricular and ventricular arrhythmias than the other groups. These results based upon observed trends suggest that cardiac rehabilitation subjects with a combination of an atypical systolic and diastolic blood pressure response to exercise may require increased medical supervision during testing, more frequent measurements of blood pressure during testing and consideration of test termination. / M.S.

Previous research on the construct and measurement of Masculine Gender Role Stress (MGRS) validates the assumption of sex differences in the appraisal of stressful situations. The present study was designed to extend the validity of the construct, MGRS, by examining its association with a set of physiological responses known as cardiovascular reactivity. Generally, such reactivity is measured in terms of systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR). Cardiovascular hyper-reactivity has been implicated as the major pathogenic mechanism through which psychological variables such as Type-A behavior and hostility may increase one's risk of coronary heart disease. A major underlying assumption of the dissertation is that the same gender-role socialization which leads to MGRS may also underlie development of Type-A behavior and hostility, and most importantly, cardiovascular hyper-reactivity. Forty-eight male undergraduate students volunteered to complete questionnaires measuring MGRS, Type-A behavior, and hostility, and participated in a one-hour laboratory session in which cardiovascular reactivity was assessed. Measures of SBP, DBP, and HR were obtained during consecutive phases of the assessment: (1) relaxation baseline, (2) the first stressor, (3) relaxation baseline, (4) the second stressor. All subjects were exposed to both stressors, a Cold Pressor Task (CPT) and a structured Masculine Threat Interview (MTI) in counter-balanced order. Subjects were divided into equal groups representing lower, middle, and upper thirds of MGRS. Results indicated that MGRS scores were significantly related to cardiovascular reactivity, specifically the SBP response. Thus, higher levels of MGRS were associated with proportionate increases in SBP reactivity. Within-subjects comparisons demonstrated no difference between stressors, the CPT versus the MTI, for SBP reactivity. Regression analyses indicated that MGRS scores were a better predictor of SBP reactivity than either Type-A behavior or hostility. Together, all three psychological variables accounted for 20% of the variance of systolic reactivity; however MGRS alone accounted for 17% of that variance. These findings add considerable support to the theoretical assumption that gender role socialization plays an important role in men's appraisal of psychological stress, and that such stress has measurable (harmful) effects on cardiovascular physiology. / Ph. D.

As cardiovascular disease remains the global leading cause of death, there is an urgent need to study the pathophysiology of the heart and to effectively evaluate cardioprotective drugs. Due to the difficulty in studying the human heart in vivo and sourcing human heart tissues, induced pluripotent stem cells (iPSCs) have provided a promising alternative for modeling cardiac diseases and evaluating candidate drugs. In recent years, computational methods, including machine learning, have given rise to a new class of tools to evaluate cardiac function more rapidly and comprehensively. In this dissertation, I develop and apply computational tools to probe the function of human iPSC-derived cardiac models (Aim 1), apply machine learning methods in the context of cardiomyocyte disease phenotyping and cardioactive drug profiling (Aim 2), and develop a pipeline for deep learning-driven cardiac fibroblast phenotypic drug discovery (Aim 3).

Atherosclerotic cardiovascular disease is a leading cause of death in the United States and worldwide. While much progress has been made in investigating dyslipidemia and inflammation regarding atherosclerotic disease, much is still unknown about the role of endogenous vascular cells in atherosclerosis. More importantly, as targeting dyslipidemia and inflammation has yielded successful therapies, can therapeutically targeting vascular dysfunction enhance existing therapies for treating cardiovascular disease? In this thesis, I sought to investigate the role of the matrix metalloproteinase, ADAMTS7, a gene implicated in atherosclerosis by genome-wide association studies (GWAS). Subsequent to the human genetic studies associating ADAMTS7 with atherosclerotic cardiovascular disease, in vivo investigations demonstrated that ADAMTS7 is proatherogenic and induced in response to vascular injury. However, the mechanisms governing ADAMTS7's function and the causal cell type responsible for producing ADAMTS7 remain unclear. To determine where ADAMTS7 expression occurs in atherosclerosis, we interrogated the largest single-cell RNA sequencing dataset of human carotid atherosclerosis. We found ADAMTS7 expression in endothelial cells, smooth muscle cells (SMCs), fibroblasts, and mast cells. We subsequently created both endothelial and SMC-specific Adamts7 conditional knockout and transgenic mice. The conditional knockout of Adamts7 in either cell type is insufficient to reduce atherosclerosis, but transgenic induction in either cell type increases peripheral atherosclerosis. In SMC transgenic mice, this increase coincides with decreased plaque stability and an expansion of lipid-laden SMC foam cells. RNA sequencing in SMCs revealed an upregulation of lipid uptake genes typically assigned to macrophages. Subsequent experiments demonstrated that Adamts7 increases SMC oxLDL uptake through Cd36. Furthermore, Cd36 expression is increased due to an Adamts7-mediated increase in Spi1, a known myeloid cell fate transcription factor. In summary, Adamts7 is expressed by multiple vascular cell types during atherosclerosis, and in SMCs, Adamts7 promotes oxLDL uptake, thereby increasing SMC foam cell and atherosclerosis. While investigating ADAMTS7, we sought to identify a cell surface persistent marker of SMCs to aid investigations into ADAMTS7. SMCs play a central role in the development of atherosclerosis due in part to their capability to phenotypically transition into either a protective or harmful state. However, the ability to identify and trace SMCs and their progeny in vivo is limited due to the lack of well-defined SMC cell surface markers. Therefore, investigations into SMC fate must utilize lineage-tracing mouse models, which are time-consuming and challenging to generate and not feasible in humans. We, thus, employed CITE-seq to phenotypically characterize the expression of 119 cell surface proteins in mouse atherosclerosis. We found that CD200 is a highly expressed and specific marker of SMCs, which persists even with phenotypic modulation. We validated our findings using a combination of flow cytometry, qPCR, and immunohistochemistry, all confirming that CD200 can identify and mark SMCs and their derived cells in early to advanced mouse atherosclerotic lesions. Additionally, we describe a similar expression pattern of CD200 in human coronary and carotid atherosclerosis. Thus, CD200 is a lineage marker for SMCs and SMC-derived cells in mouse and human atherosclerosis. In conclusion, this body of work investigated the role of vascular cells in atherosclerosis. We have identified a new marker of SMCs, adding an additional tool that can be broadly employed to investigate the vasculature. In addition, we have mechanistically unraveled how one vascular GWAS hit, ADAMTS7, can perpetuate atherosclerosis. Our findings demonstrate that ADAMTS7 can promote foam cell expansion in atherosclerosis. While more work is needed to understand the role of these SMC foam cells in atherosclerosis, our investigations thus far have demonstrated that ADAMTS7 can greatly expand these cells. As such, our work supports the development of a drug to inhibit ADAMTS7 for treating atherosclerotic cardiovascular disease.

This thesis is based on a population study conducted to explore ethnic inequalities in cardiovascular disease using Hospital Episode Statistics (HES). The Hospital Episode Statistics have significant potential for health studies for ethnic groups, due to the large number of events from minority ethnic groups, comprehensive clinical information, full England coverage and fine geographical scale. However, the percentage of Finished Consultant Episodes (FCEs) with invalid ethnicity codes is at a high level. This thesis starts by developing a record linkage method and a coding rate method to improve the data quality of ethnicity codes in the HES. This thesis then further examines ethnic inequalities in cardiovascular disease incidence in England at both national and local geographical scales. The patterns of ethnic inequalities in cardiovascular disease appear to have changed little in the last ten years. However, large variations of geographical relative risk of cardiovascular disease were observed for ethnicity-sex groups. The relationships between areal socioeconomic status measured at different geographical scales and ethnic inequalities in different types of cardiovascular disease were also explored. As there are very limited data on the mortality of minority ethnic groups in the UK, few studies have compared the incidence and outcome of cardiovascular disease from the same population. This thesis came up with some novel findings, for example, that people from minority ethnic groups, who generally have increased risk of cardiovascular disease incidence, have better cardiovascular disease survival than white people. The contribution of areal socioeconomic status, distance to treatment sites and cardiovascular disease severity and treatment to the ethnic inequalities in cardiovascular survival was examined. The relationships between socioeconomic status measured at different geographical scales and ethnic inequalities in cardiovascular disease severity and treatment were investigated in this thesis as well.

An environmental mixture is composed of multiple environmental exposures. Quantifying this joint effect on health outcomes mirrors what occurs in nature, offering significant benefits to environmental epidemiological research. However, analyzing the impact of an environmental mixture poses numerous statistical and inferential challenges. Motivated by the Strong Heart Study (SHS), a prospective cohort study of cardiovascular disease (CVD) outcomes among three American Indian communities where urine samples were collected at three visits and analyzed for concentrations of various metal exposures, this dissertation aims to improve our ability to analyze the effect of multiple, continuous, and correlated exposures with complex relationships on a health outcome using observational study data, such as the metal mixture exposure in the SHS. The contributions of this dissertation address two challenges inherent in environmental mixture analyses: modeling methods and the transportability of estimated effects. In the first project presented in this dissertation, our goal was to evaluate the performance of available modeling methods for estimating the impact of an environmental mixture on survival outcomes. While survival time outcomes (also known as time-to-event outcomes) are very common in epidemiological studies, little attention has been given to examining the performance of existing modeling methods when estimating the effect of an environmental mixture on a survival outcome. In this chapter, we identified applicable and readily available modeling methods, assessed their performance through simulations replicating various real-world scenarios, and applied the selected methods to estimate the effect of a metal mixture on CVD incidence in the SHS. We examined proportional hazards (PH) based models as well as more flexible, machine learning-style models. Our simulations found that, when the PH assumption held, the effect estimates via flexible models had higher bias and variance compared to PH methods. However, when the PH assumption was violated, this discrepancy between the methods decreased and the more flexible methods achieved higher coverage. These simulation findings underscore the importance of demonstrating the robustness of findings across various modeling approaches in environmental epidemiology. In the SHS analysis, all methods found a significant, harmful effect of the metal mixture on incident CVD. However, the more flexible approaches found larger point estimates with wider confidence bands. The second and third projects of this dissertation focus on constructing a framework for transporting an environmental mixture effect across populations. Numerous methods exist for analyzing environmental mixture effects within a population where sample data is available for. However, being able to adjust these effects based on the exposure/covariate distribution of a different target population would enable more precise estimation of the mixture effect in that population. This, in turn, allows for more accurate estimation of effects for populations distinct from those sampled. This broadens available data sources and provides significant advantages to researchers and policymakers interested in specific populations. The second project leverages causal inference concepts to formally extend the transportability literature to the environmental mixtures context. We defined a relevant intervention with favorable properties concerning the exposure concentration positivity assumption and explicitly outline the assumptions needed to transport its effect across two observational studies. To assess whether the target population is well represented in the study population sample, which is required for the positivity of population membership assumption, a matching algorithm is proposed. Subject's environmental mixture exposure profiles are incorporated into subject matching on exposures and covariates between the two populations. Simulation results demonstrate that the matching algorithm effectively detects non-overlap across populations, with well-overlapped populations yielding minimally biased transported effect estimates, while those with insufficient overlap exhibit greater bias. Applying this framework, we estimated the effects of a metal mixture on coronary artery calcification (CAC) in the SHS cohort by transporting the effects observed in the Multi-Ethnic Study of Atherosclerosis (MESA). Although CAC was not directly measured in the SHS, its importance as a subclinical indicator of advanced atherosclerosis and its link to elevated cardiovascular risk underscore the significance of exploring its relationship with metal exposures in the SHS. Despite larger effects observed in the MESA population, significant effects persisted within the SHS, providing insights for innovative strategies in preventing and treating atherosclerosis progression among American Indian populations. In the third project, we turned our focus to violations of internal and external validity exchangeability assumptions. We proposed the use of a negative control exposure analysis modeled with Bayesian Kernel Machine Regression with hierarchical variable selection to identify unmeasured confounding in the context of multiple, continuous, and correlated exposures when exposures are measured at various time points. Additionally, we developed a novel method for detecting violations of transportability assumptions by assessing the transportability of an effect within a study population. If the internal validity assumptions are plausible, then the inability to transport an effect within a study population suggests the presence of unmeasured effect modification in the study sample. Through simulations, we demonstrated the efficacy of these methods in detecting unmeasured confounding and effect modification. We applied these methods to assess the robustness of the estimated effect of a metal mixture on fasting blood glucose levels in the SHS to violations of transportability assumptions and found evidence of both unmeasured confounding and effect modification. However, the internal effect estimate remained significant and robust to unmeasured confounding.

Cardiovascular disease remains the leading causing of death worldwide. American Indians experience an elevated prevelance of cardiovascular disease (CVD) and chronic metal exposures. Determining the impact of metal exposures on CVD can inform prevention and exposure reduction strategies. This dissertation will advance environmental monitoring and biological monitoring of lead, uranium, and selenium exposures using both established biomarkers and novel epigenetic biomarkers to determine the associations of metals with CVD, leveraging the Strong Heart Study (SHS), a prospective cohort of CVD and its risk factors among American Indian adults from tribes and communities in Arizona, Oklahoma, North Dakota, and South Dakota. In Chapter 1, we discuss lead, uranium, and selenium, sources of exposure, and relevance to cardiovascular disease. This includes an overview of metal toxicokinetics and how we can assess these contaminants in both established biomarkers, including blood and urine, as well as in epigenetic biomarkers. In Chapter 2, we estimated urinary uranium concentrations from data on uranium in water among Strong Heart Family Study participants. These estimates were derived from relationships between urinary uranium and water uranium assessed in Strong Heart Family Study (SHFS) participants (n=1,356). Predictions were made using generalized linear models and included demographic and clinical participant characteristics in addition to other metal contaminants measured in water and urine. The root mean square error (RMSE) of the prediction model was 1.01, and predicted urine uranium levels were comparable (median: 0.04 μg/g creatinine, 25th-75th: 0.02-0.08 μg/g creatinine) to urine uranium measured in the SHFS (0.04 μg/g creatinine, 0.02-0.07 μg/g creatinine). These findings emphasize the contribution of uranium in water to urine uranium (reflecting internal dose), and demonstrate the relevance of estimating metal contaminants in urine for the SHS to inform relationships with health effects. In Chapter 3, we evaluated whether urinary uranium concentrations were associated with measures of cardiac geometry and functioning among 1,332 American Indian youth and young adults from the SHFS. Transthoracic echocardiography and blood pressure was assessed at baseline (2001-2003) and a follow-up visit (2006-2009). We estimated mean differences in measures of cardiac geometry and functioning at baseline and follow-up using linear mixed effect models with random intercept and slope over time. In fully adjusted models, a log-doubling of urinary uranium was positively associated with left ventricular (LV) mass index (mean difference: 0.49 g/m2, 95% CI: 0.07-0.92 g/m2), left atrial systolic diameter (0.02 cm, 0.01-0.03 cm), and stroke volume (0.66 mL, 0.25-1.08 mL) at baseline. At follow-up, uranium was associated with increases in left atrial diameter (0.02 cm, 0.01-0.03 cm), pulse pressure (0.28 mmHg, 0.05-0.52 mmHg), and incident LV hypertrophy (OR: 1.25, 95% CI: 1.06, 1.48). These findings support the need to determine the potential long-term clinical and subclinical cardiovascular effects of chronic uranium exposure in the general population, and the need for future strategies to reduce exposure. In Chapter 4, we evaluated if blood lead was associated with CVD incidence and mortality in 1,818 adult American Indian participants. This study estimated the risk of incident CVD and CVD deaths in models adjusted for demographic, lifestyle, and cardiovascular risk factors. Blood lead levels in American Indian adults were associated with increased risk of CVD and coronary heart disease (CHD) incidence and mortality. The hazard ratio (HR) (95% CI) of mortality per change across the 80th-20th quantiles in blood lead was 1.15 (1.02-1.30) for CVD overall and 1.22 (1.08-1.37) for CHD. The corresponding HR was 1.11 (1.01-1.22) for incident CVD and 1.12 (1.00-1.25) for incident CHD. These findings contribute to the evidence of lead as a CVD risk factor at low levels and highlight the importance of further reducing lead exposure in communities across the United States, including American Indian communities. In Chapter 5, we leveraged novel epigenetic biomarkers of lead exposure to investigate their association with cardiovascular disease (CVD) incidence and mortality among 2,231 participants of the Strong Heart Study. Blood DNA methylation was measured using the Illumina MethylationEPIC BeadChip at baseline (1989-1991) and epigenetic biomarkers of lead levels in blood, patella, and tibia were estimated using previously developed biomarkers of DNA methylation at specific CpG sites. In adjusted models, the hazard ratio (HR) (95% CI) of CVD mortality per doubling increase in lead epigenetic biomarkers were 1.42 (1.07-1.87) for tibia lead, 1.22 (0.93-1.60) for patella lead, and 1.57 (1.16-2.11) for blood lead. The corresponding HRs for incident CVD were 0.99 (0.83-1.19), 1.07 (0.89-1.29), and 1.06 (0.87-1.30). The association between the tibia lead epigenetic biomarker and CVD mortality was modified by sex (interaction p-value: 0.014), with men at increased risk (HR: 1.42, 95% CI:1.17-1.72) compared to women (HR: 1.04, 95% CI:0.89-1.22). These findings support that epigenetic biomarkers of lead exposure may capture some of the disease risk associated with lead exposure. In Chapter 6, we investigated the association between urinary selenium levels and DNA methylation (DNAm) among 1,357 participants free of CVD and diabetes in the SHS. Selenium concentrations were measured in urine (collected in 1989-1991) using inductively coupled plasma mass spectrometry. DNAm in whole blood was measured cross-sectionally using the Illumina Methylation EPIC BeadChip (850K) Array. We used epigenome-wide robust linear regressions and elastic net to identify differentially methylated CpG sites associated with urinary selenium levels. Across 788,368 CpG sites, five differentially methylated positions (DMP) (cg00163554, cg18212762, cg25194720, cg11270656, cg00886293) were significantly associated with Se in linear regressions after accounting for multiple comparisons (false discovery rate p-value: 0.10). The top associated DMP (cg00163554) was annotated to the Disco Interacting Protein 2 Homolog C (DIP2C) gene, which relates to transcription factor binding. Future analyses should explore these relationships prospectively and investigate the potential role of differentially methylated sites with disease endpoints. In Chapter 7, we evaluated if declines in blood lead were associated with changes in systolic and diastolic blood pressure in adult American Indian participants from the SHFS (n=285). Using generalized estimating equations, a significant non-linear association between declines in blood lead and declines in systolic blood pressure was detected, with significant linear associations where blood lead decline was 1 µg/L or higher. These findings suggest the need to further study the cardiovascular impacts of reducing lead exposures and the importance of lead exposure prevention. In conclusion, we find that established biomarkers of metal exposure reflecting internal dose such as blood and urine, as well as epigenetic biomarkers of metals exposures, were associated with subclinical CVD and CVD incidence and mortality. Findings concerning blood lead emphasize that low levels of lead remain relevant for CVD, and declines in blood lead even when small (1.0-10.0 µg/L), were associated with reductions in systolic blood pressure. Novelly, we present that urinary uranium levels were adversely associated with measures of cardiac geometry and left ventricular functioning among American Indian adults, and that future attention must be paid to investigating associations with subclinical disease. We also find utility in using epigenetic biomarkers to capture CVD risk, as tibia and blood epigenetic biomarkers of lead, were associated with increased risk of CVD mortality, and urinary selenium was associated with distinct changes in DNAm. Although further work must further validate these epigenetic biomarkers in different populations, future work must continue to investigate these epigenetic biomarkers given their potential to capture CVD risk.

Thesis (PhD)--Stellenbosch University, 2015. / ENGLISH ABSTRACT: Endothelial injury and dysfunction precede the development of cardiovascular diseases. The endothelium may be regarded as the first line of defence against inflammation / obesity-induced vascular injury, therefore gaining more information on the mechanisms of injury and response to injury, as well as modulating endothelial function may be key in the prevention of cardiovascular diseases. Endothelial cells differ in structure and function, therefore endothelial heterogeneity may be relevant when investigating endothelial function and dysfunction. Understanding endothelial heterogeneity in response to pathophysiological stimuli may be of significance in the prevention of cardiovascular diseases. Oleanolic acid (OA), a plant-derived triterpenoid, has been shown to possess endothelio-protective properties; however, its role in reversing endothelial injury is poorly understood. This study investigated endothelial heterogeneity between aortic endothelial cells (AECs) and cardiac microvascular endothelial cells (CMECs) at baseline and in response to an inflammatory insult via the cytokine, tumour necrosis factor-alpha (TNF-α). An in vitro model of endothelial injury was developed by treating AECs and CMECs with 20 ng/ml TNF-α for 24 hours. Endothelial heterogeneity was investigated by comparing intracellular nitric oxide (NO) and reactive oxygen species (ROS) production, protein expression and phosphorylation, and large-scale protein expression and regulation in AECs and CMECs. The experimental techniques included flow cytometry, western blots and proteomic analyses. An ex vivo model of endothelial injury was included to investigate vascular function in aortic rings from lean and high fat diet (HFD) rats. The role of OA in reversing TNF-α-induced injury and modulating vascular function in the ex vivo model was investigated. Although baseline NO-levels were similar between AECs and CMECs, heterogeneity was observed with regards to the NO biosynthetic pathway in terms of increased eNOS expression in CMECs. Baseline ROS levels were heterogeneous between AECs and CMECs, interestingly CMECs possessed higher anti-oxidant capacity. An in vitro model of TNF-α-induced injury was confirmed by decreased NO-levels, increased ROS-levels and necrosis, up-regulation of apoptotic proteins and activation of inflammatory pathways in AECs and CMECs. Here, heterogeneity between AECs and CMECs was also observed: endothelial activation was mediated through different proteins in AECs (CD9 molecule, galectin) and CMECs (ICAM-1 and IL-36α). Apoptosis was mediated by caspase 3 in AECs and Bid in CMECs. AECs appeared to advance to a dysfunctional state shown by up-regulation of endothelin-converting enzyme and angiotensin II-converting enzyme, while CMECs maintained an activated state. OA reversed TNF-α-induced injury through restoring NO-production, decreasing ROS-production in both AECs and CMECs, and inhibiting necrosis in AECs. In the ex vivo model of injury, aortic rings from 16-week HFD rats showed a pro-contractile response to phenylephrine-induced contraction, a response that was reversed by OA. In conclusion, we demonstrated novel findings with regards to endothelial heterogeneity between AECs and CMECs under baseline and TNF-α-treated conditions. Although reduced NO-bioavailability may be the hallmark of endothelial dysfunction, signalling pathways mediating endothelial injury may differ between cell types as was shown in this study. We demonstrated that OA possess protective properties in AECs and CMECS, an observation which was translated to the ex vivo model. / AFRIKAANSE OPSOMMING: Endoteelbesering en –disfunksie gaan die ontwikkeling van kardiovaskulêre siektes vooraf. Die endoteel word as die eerste linie van verdediging teen inflammasie / vetsug-geïnduseerde vaskulêre skade beskou; dus is die ontginning van nuwe inligting betreffende die meganismes van en respons tot besering, asook die modulering van endoteelfunksie essensieël in die voorkoming van kardiovaskulêre siektes. Endoteelselle verskil t.o.v. struktuur en funksie, en dus is endoteel-heterogeniteit relevant tydens die ondersoek van endoteelfunksie en –disfunksie. ‘n Beter begrip van endoteel-heterogeniteit in die respons tot patofisiologiese stimuli kan betekenisvol tot die voorkoming van kardiovaskulêre siektes bydra. Oleanoliese suur (OA), ‘n triterpenoïed afkomstig van plante is voorheen bewys om endoteelbeskermende eienskappe te besit; die rol van OA in die omkering van endoteelbesering is egter minder bekend. Hierdie studie het endoteel-heterogeniteit tussen aorta endoteelselle (AECs) en hart mikrovaskulêre endoteeelselle (CMECs) by basislyn en in respons tot ‘n inflammatoriese besering via die sitokien, tumor nekrose faktor-alfa (TNF-α), ondersoek. ‘n In vitro model van endoteelbesering is ontwikkel deur AECs en CMECs met 20 ng/ml TNF-α vir 24 uur te behandel. Endoteel-heterogeniteit was ondersoek deur intrasellulêre stikstofoksied (NO) en reaktiewe suurstofspesies (ROS) produksie, proteïenuitdrukking en fosforilering, en grootskaalse proteïenuitdrukking en regulering in AECs en CMECs te vergelyk. Die eksperimentele tegnieke het ingesluit: vloeisitometrie, western blots en proteomika. ‘n Ex vivo model van endoteelbesering was ook ingesluit deur die vaskulêre funksie in aortaringe van normale en hoë vet dieet-gevoerde (HFD) rotte te meet. Die rol van OA in die omkering van TNF-α-geïnduseerde besering en modulering van vaskulêre funksie was in hierdie model is ondersoek. Alhoewel basislyn NO-vlakke vergelykbaar was in AECs en CMECs, is heterogeniteit wel aangetoon m.b.t. die NO biosintese pad met verhoogde eNOS uitdrukking in die CMECs. Basislyn ROS-vlakke was verskillend in AECs en CMECs en die CMECs het hoër anti-oksidant kapasiteit getoon. ‘n In vitro model van TNF-α-geïnduseerde besering is bevestig met die waarneming van verlaagde NO-vlakke, verhoogde ROS-vlakke en nekrose, opregulering van apoptotiese proteïene en aktivering van inflammatoriese paaie in AECs en CMECs. Hier was heterogeniteit ook opmerkbaar: endoteelaktivering was deur verskillende proteïene in AECs (CD9 molekule, galektien) en CMECs (ICAM-1, IL-36α) bemiddel. Apotose was deur kaspase 3 in AECs en Bid in CMECs bemiddel. Dit het geblyk dat AECs tot ‘n staat van endoteeldisfunksie gevorder het met die opregulering van endotelien-omsettingsensiem en angiotensien II-omsettingsensiem, terwyl CMECs eerder ‘n geaktiveerde staat gehandhaaf het. OA het TNF-α-geïnduseerde besering omgekeer deur NO-produksie te herstel, ROS-produksie te onderdruk in beide AECs en CMECs, en nekrose te inhibeer in AECs. In die ex vivo model van besering, het aortaringe van 16-week HFD rotte ‘n pro-kontraktiele respons tot fenielefrien-geïnduseerde kontraksie getoon, wat deur OA omgekeer is. Ten slotte, nuwe bevindinge is waargeneem m.b.t. endoteel-heterogeniteit tussen AECs en CMECs onder basislyn en TNF-α-behandelde omstandighede. Alhoewel verlaagde NO-biobeskikbaarheid die waarmerk van endoteeldisfunksie is, het hierdie studie getoon dat seintransduksiepaaie wat endoteelbesering medieer verskillend is tussen seltipes. Die studie het verder ook gedemonstreer dat OA beskermende eienskappe toon in AECs en CMECs, ‘n waarneming wat ook in die ex vivo model aangetoon kon word.

published_or_final_version / Community Medicine / Master / Master of Public Health

The influence of autonomic activation in response to controllable versus noncontrollable stress, anger imagery induction, and relaxation imagery was studied among 80 participants between the ages of 18 and 34. Participants differed in level of trait hostility as assessed by the Irritability Subscale of The Buss-Durkee Hostility Inventory (Buss & Durkee,1957) and the Ho scale of the Cook-Medley Hostility Inventory (Cook & Medley, 1954). Groups were further subdivided with regards to either having a positive family history of cardiovascular disease or having no significant history. Results were obtained through analyses of electrocardiograph R-R intervals which produced an index of autonomic nervous system activation. Findings supported hypotheses involving the relations between autonomic balance and stress and hostility for the female and male populations. Among both populations, parasympathetic regulation was diminished during anger induction for individuals with high levels of trait hostility and having a family history of cardiovascular disease. Similar results were obtained for men during relaxation imagery induction.