Familial hypercholesterolemia (FH) is an autosomal dominant disorder in which the primary defect is a mutation in the LDL receptor. Heterozygous FH is among the most common inborn errors of metabolism and remains as the best example of an inherited defect causing premature coronary artery disease (CAD). This thesis describes the physical and biochemical characteristics of heterozygous FH in a large cohort consisting of 208 women and 156 men. The influence of both genetic and environmental factors on the clinical expression of FH were investigated to better understand the phenotypic variation within FH and thus improve the prediction and treatment of CAD in affected individuals. The general incidence of CAD in this population was lower compared to previous reports but the differences between the sexes were expected. It was shown that men had a much higher frequency of CAD (31%) compared to women (13%) despite having lower concentrations of total and LDL cholesterol. In addition, the average age of onset of coronary symptoms was delayed in females, 55 years compared to 48 years for males. A greater risk of developing CAD for men was associated with low levels of HDL cholesterol and a history of smoking. In women, however, CAD was associated with elevated triglyceride levels and the presence of hypertension. In order to efficiently assess the influence of the co-inheritance of the apolipoprotein E polymorphism in this large FH population, a novel apo E phenotyping procedure was developed. Phenotypes were determined directly from plasma which was neuraminidase treated, delipidated and focused in polyacrylamide minigels. The accuracy of this method was confirmed by making a comparison to the established procedure of phenotyping by isoelectric focusing of delipidated VLDL. The low cost, speed and simplicity of the minigel methodology provided ideal conditions to phenotype a large patient population. The frequencies of the ɛ2, ɛ3 and ɛ4 alleles of apolipoprotein E in 125 unrelated FH subjects did not differ significantly from the normal population. In addition, there was no apparent relationship between apo E4 and the concentration of any of the parameters in the plasma lipid profile. However, the presence of the E2 isoform was associated with significantly elevated triglycerides in both sexes. From this study, it is evident that the mutant FH gene exerts its effect within a system of interacting environmental and polygenic factors that are known to modify atherosclerotic risk. It has been established that the dissimilarity in the frequency of CAD between men and women is related to differences between the impact of known risk factors and the incidence of CAD. Therefore, the importance of the influence of these risk factors and the differences between men and women should be emphasized when treating and predicting the development of CAD in patients with FH. / Medicine, Faculty of / Pathology and Laboratory Medicine, Department of / Graduate

This research explored the understanding of coronary heart disease among the South Asian Migrant men in the UK. The objectives of this study are: • To explore migrant South Asian men's understanding of the risks involved with coronary heart disease in the UK • To relate their understanding in the context of current health care policy • To suggest ways to provide culturally sensitive health promotion programs to these groups. A phenomenological perspective using qualitative research methodology and focus group interviews were used to obtain a more precise and in-depth understanding of the risks involved with coronary heart disease. In total 83 men were recruited. 13 focus groups were conducted in three different areas across the country which had a significant South Asian population. Three themes emerged from the analysis of the interviews: Psychosocial factor, conventional risk factors & health care experiences. These themes reflected the men's understanding of the risks Involved with coronary heart disease In the UK. According to Williams et al, (2007 & 2009), information about psychosocial risk profiles in UK South Asians is limited and that there is an increased possibility that psychosocial related factors contribute to increased vulnerability to coronary heart disease in South Asian in the UK. This study concludes with the importance of recognizing that not all South Asians are the same and that health professionals should look beyond the context of religious, and ethnic background and focus on individual men.

The full text of this thesis/dissertation is not available online. Please <a href="mailto:upetd@up.ac.za">contact us</a> if you need access. Read the abstract in the section 00front of this document. / Thesis (DPhil (Human Movement Scinece))--University of Pretoria, 2000. / Arts, Languages and Human Movement Studies Education / unrestricted

Gene expression is regulated by local genetic sequence, and researchers have identified thousands of common genetic variants in the human population that associate with altered gene expression. These expression quantitative trait loci (eQTLs) often co-localize with genome wide association study (GWAS) loci, suggesting that they may hold the key to understanding genetic effects on human phenotype and cause disease. eQTLs are enriched in cis-regulatory elements, suggesting that many affect gene expression via non-coding mechanisms. However, many of the discovered loci lie in noncoding regions of the genome for which we lack understanding, and determining their mechanisms of action remains a challenge. To complicate matters further, genetic variants may have varied effects in different tissues or under different environmental conditions. The research presented here uses statistical methods to investigate genetic variants’ mechanisms of actions and context specificity. In Chapter 1, we introduce eQTLs and discuss challenges associated with their discovery and analysis. In Chapter 2, we investigate cross-tissue eQTL and gene expression patterns, including for GWAS genes. We find that eQTL effects show increasing, decreasing, and non-monotonic relationships with gene expression levels across tissues, and we observe higher eQTL effects and eGene expression for GWAS genes in disease-relevant tissues. In Chapter 3, we use the natural variation of transcription factor activity among tissues and between individuals to elucidate mechanisms of action of eQTL regulatory variants and understand context specificity of eQTL effects. We discover thousands of potential transcription factor mechanisms of eQTL effects, and we investigate the transcription factors’ roles with orthogonal datasets and experimental approaches. Finally, in Chapter 4, we focus on a locus implicated in coronary artery disease risk and unravel the likely causal variants and functional mechanisms of the locus’s effects on gene expression and disease. We confirm the locus’s colocalization with an eQTL for the LIPA gene, and using statistical, functional, and experimental approaches, we highlight two potential causal variants in partial linkage disequilibrium. Taken together, this work develops a framework for understanding eQTL context variability and highlights the complex genetic and environmental contributions to gene regulation. It provides a deeper understanding of gene regulation and of genetic and environmental contributions to complex traits and disease, enabling future research surrounding the context variability of genetic effects on gene expression and disease.

L’infarctus du myocarde est l’une des principales causes de morbi-mortalité dans les pays développés, malgré l’amélioration enregistrée dans la prise en charge thérapeutique de cette urgence coronaire. Le stress oxydant est un facteur impliqué dans la physiopathologie de l’IDM. Notre étude a montré la diminution des capacités antioxydantes chez des patients hospitalisés pour un IDM aigu. Une partie de notre étude a été consacrée pour explorer le système Peroxyredoxine Thioredoxine. Il s’agit d’un système antioxydant majeur impliqué dans la régulation des voies d’apoptose. La connaissance des mécanismes moléculaires responsables des lésions myocardiques lors d’une ischémie, constitue l’une des avancées importantes dans la compréhension de la physiopathologie des syndromes coronaires aigus. / Myocardial infarction is the leading cause of death in developed nations despite of recent advances in the management of this disease. Oxidative stress is involved in the physiopathology of Myocardial Infarction. Our study showed a decreased antioxidant activities in patients with Acute Myocardial Infarction. A part of the present study was designed to explore Peroxiredoxin Thioredoxin activity. It’s considered as a major antioxidant system and it control hydrogen peroxide levels which mediate the signal transduction, including apoptosis signal. Molecular mechanisms underlying the oxidative stress toxicity in cardiomyocytes have to be more elucidated and may help the evolving of therapeutic care strategies of coronary heart disease.

No description available.

Heart disease, including principally coronary heart disease (CHD) remains the top cause of mortality in the United States among adults ages 35 and older. Disparities in CHD mortality between socially advantaged and disadvantaged groups, such as whites and blacks have persisted for decades. These social gaps persist despite advances in treatments, preventive measures, and decreases in population prevalence of smoking that have done much to reduce the burden of CHD overall. While these differences in disease burden have been well documented, there is a poor understanding of what interventions might narrow these differences. An equity-efficiency tradeoffs (EET) framework is a useful lens through which to consider this problem. Tradeoffs between equity of intervention efforts and efficiency of the returns on such efforts arise when public health interventions are deployed across groups of unequal socioeconomic position. While such interventions may achieve overall and intra-group improvement, this improvement may come at the expense of stable or widening inter-group differences. Aiming to add to this literature, we took three approaches. First, we critically assessed the literature in order to identify and summarize prior work on EETs across cardiovascular outcomes. We aimed to identify the questions that empirical studies should answer for a given policy, from an EET perspective. Second, recognizing both that tobacco taxation is an effective policy intervention on CHD, and that we have little evidence from United States based studies that it influences racial gaps in CHD we used as an example this policy intervention to examine the treatment efficiency inherent in raising tobacco taxes from an equity lens. We conducted an empirical study to estimate the treatment effectiveness of US tobacco taxation on smoking and CHD mortality. Third, we simulated the equity and treatment efficiency effects of pharmaceutical (Statins), taxation (tobacco) and early education interventions on CHD mortality, and racial gaps in CHD mortality. Our scoping review of EETs in cardiovascular disease (Chapter 2) yielded a very small number of studies (n=6), that explicitly engaged equity and efficiency, and provided information on their trade-offs in the context of CVDs. Despite a paucity of evidence, we identified 2 important lessons: (1) movement toward equity in the context of interventions on those with a high burden of CHD risk factors may be achieved by targeting deprived populations. Second, pairing these “high risk” with structural interventions can provide substantial movement toward not only efficiency, but also equity. Our nationally representative observational, state-level study of the effects of tobacco taxation on smoking prevalence and CHD mortality by race and gender (Chapter 3) showed that between 2005 and 2016, tobacco taxes were associated with reductions in both outcomes. The strongest reductions in smoking prevalence were observed among black non-Hispanic women, while an increase was observed among black non-Hispanic men. Our simulation study (Chapter 4) showed that the equity and efficiency effects of population health interventions in the context of reducing racial disparities in CHD may vary by gender. Among men, compared to no intervention, an education intervention was associated with the greatest reduction in racial disparities in CHD mortality, while among women, a $3 tobacco tax intervention was associated with the greatest reduction in racial disparities in CHD mortality. Additionally, among men, tobacco taxes were an equity lose intervention, while for women, in contrast, tobacco taxes were nearly always a win-win intervention. Conversely, compared to tobacco taxes, statins are in some cases a win-win intervention for men, and in all cases a lose-lose intervention for women. Our findings support the utility of an EET lens in the reduction of racial disparities in health, and point to the need for more scholarship and broader integration of this lens into public health practice. Consideration of the interplay between equity and efficiency in population health interventions offers a deeper understanding of intervention effects than the consideration of either dimension alone. In some cases, we need not trade equity for efficiency in the reduction of racial inequities in health.

Aims The associations of moderate alcohol consumption, sleep duration, and tobacco smoking with coronary heart disease (CHD) among patients with type 2 diabetes mellitus (T2D) are not clearly clarified. The aims of the study were to evaluate the associations of lifestyle factors, hypertension, obesity, depression and sleep duration with CHD development among patients with T2D, and particularly, to examine the gender differences in risk factors for CHD. Methods A total of 2335 T2D adults were selected from the 2012 National Health Interview Survey. Weighted univariate and multiple logistic regression analyses were used to estimate the odds ratios with 95% confidence intervals. Results The CHD prevalence among patients with T2D was 14.2% (18.1% and 10.4% for males and females, respectively), which increased with age (10.3% and 19.6% for age groups 18–64 and 65+, respectively). After adjusting for other factors, weighted logistic regression analyses showed that CHD among patients with T2D was significantly associated with being male, older age, past smoking, long sleep duration, hypertension, and high cholesterol level. Furthermore, the significant association of older age, past smoking, hypertension and high cholesterol level were observed particularly in males, while the association of long sleep duration with CHD was only observed in females. Hypertension was associated with CHD for both genders. Conclusions Gender, age, past smoking, long sleep duration, hypertension and high cholesterol level were significantly associated with CHD among T2D patients; however, such associations differed by gender. Such gender disparities should be considered in the prevention and treatment of T2D.

This experiment investigated sex differences in dynamic functional cerebral laterality effects on cardiovascular reactivity and dichotic listening in response to a stressor (a cold pressor). 120 right-handed undergraduate men (N = 60) and women (N = 60) underwent physiological measurements of systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR) before and after exposure to the cold pressor and a phonemic dichotic listening task. Functional cerebral laterality was assessed through the administration of the phonemic dichotic listening task. Group differences in dynamic functional cerebral laterality were predicted. Findings indicated a sex by focus interaction effect where men's, but not women's, systolic blood pressure increased significantly when focusing on sounds presented at the left ear during the dichotic listening task. Also, a compartmentalized, dynamic response in dichotic listening test performance was evidenced in both men and women (as both experienced increased accuracy at the right, but not left, ear), brought about as a function of the cold pressor. Men and women both evidenced increased cardiovascular reactivity, with men experiencing significantly more cardiovascular reactivity (SBP) than women in response to cold pressor pain. Women were also able to identify significantly more speech sounds presented to the left ear than men, and they were able to dynamically increase accuracy at the targeted ear identified within each focus group (left or right). Speech sounds processing (dichotic listening task) significantly decreased men's, but not women's, systolic blood pressure. These results contribute to the literature on sex differences in functional cerebral laterality. / Master of Science

The purpose of this study was to examine the effects of socio- viii demographic characteristics, knowledge of coronary heart disease and behavior variables on blood cholesterol concentration among 218 selected subjects in northern Utah connnunities. The data were obtained from physicians' medical charts and a survey specifically designed for this study. A model was developed from an intensive review of literature and the current state of theoretical and empirical knowledge and was tested by means of path analysis. The model contained fourteen variables including familial coronary heart disease heredity, sex, age, the presence of disease(s), educational attainment, special dietary regimen, occupation, knowledge about coronary heart disease, Type A/B behavior patterns, attitude toward low-fat, low-cholesterol diets, saturated fat calorie intake, energy expenditure, relative body weight, and blood cholesterolconcentration. The model was evaluated for the entire sample as well as two subsamples of males and females. It was found that there was a strong causal relationship between the level of education and knowledge about coronary heart disease (CHD), and between its knowledge and attitude toward low-fat, low-cholesterol diets (less atherogenic diets). Furthermore, it was observed that a favorable positive attitude toward low-fat, low-cholesterol diets served directly to decrease the relative body weight. On the other hand, estimated expenditure of total energy was increased with increasing knowledge about coronary heart disease and in physically active occupations. There was a negative association between the estimated total energy expenditure and blood cholesterol concentration, while a weak positive relationship of relative body weight and saturated fat intake on cholesterol concentration in the blood was observed. Not only knowledge about coronary heart disease had a direct influence on attitude, but also age had a positive causal effect on attitude toward low-fat, low-cholesterol diets. The direct association of familial coronary heart disease heritability on blood cholesterol concentration was the strongest among other variables, followed by special diets, age, total energy expenditure, and saturated fat intake. About 28% of the variations in the blood cholesterol concentration among the entire sample could be explained by eleven variables combined compared with 36% for females and 23% for males. It was shown in the likelihood ratio test that the influence of social and demographic characteristics, knowledge about coronary heart disease, and behavior variables on blood cholesterol concentration was not significantly different between male and female samples. In conclusion, this research suggests the direction and magnitude of causal relationships between socio-demographic characteristics, knowledge of coronary heart disease and behavior variables and serum cholesterol concentration. Therefore, the findings of this study indicate the potential value of educational programs for the coronary heart disease prevention.