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Introduction: Atherosclerosis remains asymptomatic until it progresses to cause flow-limiting disease. Identifying patients at high risk in the early stages of the atherosclerotic process may allow modification of cardiovascular risk by effective preventive strategies. Various non-invasive tests have been studied and have shown promising results in predicting future adverse cardiovascular events. The objective of this study was to establish the carotid ultrasonographic markers that best correlate with angiographic coronary artery disease (CAD) and the relationship between left ventricular geometry, carotid atherosclerosis, biomarkers and CAD in patients with unobstructed coronary arteries, chronic stable angina (CSA) and acute coronary syndromes (ACS). Methods: Carotid ultrasound examination, echocardiography and serum biomarker estimation were performed in consecutive patients who underwent coronary angiography for evaluation of stable or acute chest pain. Results: A total of 146 subjects were recruited into the study with a mean age of 56.9 ± 10.6 (range 29 to 85) years; 120 were men (82%) and 26 (18%) women. Twenty-one percent of the study population had unobstruced coronaries, 42% had stable CAD and 37% had presented with ACS. There was no significant difference in the carotid intima media thickness (CIMT) measurements between the three groups. CIMT correlated with abnormal left ventricular geometry but not with the presence or severity of CAD. The presence of carotid plaque and plaque score correlated with obstructive CAD, but was not significantly different between stable CAD and ACS patients. There was a trend towards more echogenic plaque in the stable CAD group. The composite score of IMT and plaque was positively correlated with the presence and severity of CAD. The averaged myocardial peak systolic and early diastolic velocities were significantly lower in those with obstructive CAD. CRP and osteopontin levels were higher in the ACS patients. Conclusions: Carotid plaque and not CIMT was associated with angiographic coronary artery disease. Averaged systolic and early diastolic myocardial velocities by tissue doppler imaging correlated with obstructive CAD. Novel serum biomarkers are promising and further studies are needed.

Stroke is the 2nd leading cause of death in the UK and worldwide. 150,000 people have a stroke each year in the UK (ischaemic stroke being the most common) and a significant proportion of NHS resources go towards the treatment of these individuals (~£2.8 billion). Twin and family history studies have shown that having affected relatives makes you between 30 and 76% more likely to suffer a stroke, suggesting that there is a genetic component to the disease. So far, no genes have been convincingly associated with stroke. Intermediate traits may be useful tools for identifying genetic factors in complex disease. For stroke, two commonly used intermediate traits are carotid intima-media thickness (CIMT) and white matter hyperintensities (WMHs), which both show high heritabilities. These traits have both been studied widely for associations with many candidate gene polymorphisms. In this thesis I systematically reviewed the literature for all genetic association studies of these two traits. Where particular associations have been studied in large numbers I meta-analysed the available data, developing novel methods for meta-analysis of genetic association data. I found there was substantial heterogeneity and small study bias in the literature and most polymorphisms have still been studied in too small numbers to make accurate conclusions. Apolipoprotein E (APOE) ε is the only polymorphism which shows a consistent association with CIMT, even when only the largest studies are analysed (MD 8μm (95% CI 6 to 11) between E4 and E3, and E3 and E2). No polymorphism has shown a convincing association with WMHs and interestingly APOE appears unlikely to be associated with this trait. This is consistent with previous work that shows that APOE is associated with large artery but not small artery stroke. Taking this hypothesis I attempted to investigate the association of APOE comparing patients who have had a large artery stroke with those who have had a small artery stroke in the Edinburgh Stroke Study cohort. However, genotyping of this polymorphism failed and I present investigatory analyses of problems from the genotyping laboratory.

This study examined racial/ethnic differences in pre-clinical disease, social support, and tested whether social support was a moderator of racial/ethnic differences in subclinical atherosclerosis. Participants were NHWs, NHBs, and Latinos (n = 283) from the baseline and cross-sectional sample of the North Texas Heart Study. Results from unadjusted models showed no significant racial/ethnic differences for common or bifurcation intima-media thickness (cIMT). However, unadjusted models for cIMT showed a main effect for race/ethnicity F(2, 229) = 3.12, p = .046, partial η2 = .027, with Latinos demonstrating significantly greater internal cIMT compared to NHB but not NHWs. In minimally adjusted models, there was a main effect for race/ethnicity, F(2, 227) = 3.10, p = .047, partial η2 = .027, with significantly greater internal cIMT in Latinos compared to NHBs but not NHWs. In fully adjusted models, racial/ethnic differences in cIMT were attenuated. Contrary to study hypotheses, no racial/ethnic differences in social support were found and social support was not a moderator of racial/ethnic differences in subclinical disease. In the North Texas Heart Study, few racial/ethnic differences emerged, with fully adjusted risk factor models accounting for these differences.

Cardiovascular disease is the leading cause of death in the United States. Chronic short sleep duration is also a significant public health problem and has been linked to several markers and outcomes of cardiovascular disease. To date, inconsistency of assessments of sleep duration and insufficiency, use of covariates, and cardiovascular disease measurement across studies limits strong conclusions about the relationship between sleep duration, sleep insufficiency, and cardiovascular disease. The current study examined the association between sleep duration, sleep insufficiency, and a marker of preclinical coronary heart disease (i.e., carotid intima-media thickness) in a community sample using a cross-sectional design. Some evidence for a relationship between sleep duration and cIMT was found, with longer sleep duration predicting higher cIMT in some segments. Additionally, the interaction between sleep duration and sleep insufficiency was significant. However, neither of these effects were significant after adjusting for age and in some cases race/ethnicity, suggesting demographics may explain this association. Actigraphy and sleep diary duration assessments demonstrated significantly different correlations with cIMT in some segments, suggesting the nature of the assessment method may impact the strength or direction of the relationship between sleep duration and cIMT. Limitations and future directions are discussed.

Abstract: Modifiable cardiovascular disease (CVD) risk factors, such as adiposity, are already associated with atherosclerotic progression in childhood. Less is known about whether physical activity (PA) is associated with progression of atherosclerosis in non-clinical samples of children. This cross-sectional study used baseline data from 426 eight- to ten-year-olds from the Quebec Adiposity and Lifestyle Investigation in Youth (QUALITY) Study to assess associations between PA and carotid intima media-thickness (cIMT) – a surrogate marker of atherosclerosis, and potential effect modification by adiposity and fitness. Results of this thesis should be interpreted with caution, as validity of cIMT measurement from the QUALITY Study is currently being investigated because of suboptimal reliability and precision of ultrasound equipment. PA was not associated with cIMT in this at-risk sample. Analyses in adiposity or fitness categories showed potential differences by groups. More structured and high-intensity PA may be required to slow atherosclerotic progression between childhood and adulthood.

BACKGROUND: There are many studies that have documented the increasing impact of stress and anxiety on an individual’s health and well-being. Everyone handles stress and anxiety differently with these conditions having varying physiological effects. To better recognize whether or not a person may need help in tackling these conditions, scholars have developed reliable validated instruments. Two prominent instruments that effectively assess stress and anxiety levels are the Perceived Stress (PSS) and Generalized Anxiety Disorder (GAD-7) scales. Furthermore, the literature has shed light onto the importance of the carotid intima-media thickness (c-IMT) measurement as a tool in evaluating the risk of cardiovascular disease. After all, heart disease has been reported as being the number one killer of Americans in recent years. The specific aims of this study were to determine if there was an association between perceived stress / generalized anxiety and c-IMT (static association), and also if higher levels of perceived stress / generalized anxiety result in a significant increase in c-IMT (changes over time). METHODS: Data was collected on about 700 participants comprised of employees from Emory University in Atlanta, Georgia. At baseline, six, twelve, and twenty-four months, the largest number of participants had completed and calculated their scores on the PSS and GAD-7 scales. At these same time points, participants had their IMT measured and recorded for the left and right common carotid arteries by a trained sonographer of the Emory Predictive Health Institute. Due to incomplete measurements and scores, only 228 participants were included for statistical analyses. This was still considered a suitable sample size given that this study only involved four measurement time points. Various statistical models were fitted for the data. All variables in the models were treated as categorical except for time which was continuous. Four separate models were built that included the variables perceived stress, age group, gender and time. In a similar manner, four models were built that included the variables generalized anxiety, age group, gender and time. AIC values, -2 log-likelihoods, partial correlations, p-values, and other relevant information were reported for these models. All statistical analyses were performed using the Statistical Analysis System (SAS), version 9.2. RESULTS: The mean c-IMT measurements for the Emory participants were higher than established normal ranges. A strong correlation existed between the PSS and GAD-7 two-year averages when treated as continuous variables (.7316, p CONCLUSIONS: Failure to control anxiety could lead to c-IMT soaring to dangerous levels resulting in a myocardial infarction and/or cerebrovascular accident. Individuals should engage in healthy lifestyle practices that lower stress and anxiety levels to decrease the chances of cardiovascular disease. Based on this study’s findings, a person can certainly use their c-IMT readings, as well as their perceived stress and generalized anxiety scores, as indicators that lifestyle modifications may be needed.

Von Willebrand factor (VWF) is considered a reliable marker of endothelial damage. Plasma levels of VWF were measured in 857 middle-aged subjects (80.4% men) free of clinically overt atherosclerotic disease, in relation to cardiovascular risk factors, carotid intima-media thickness (IMT) and microalbuminuria, two established surrogate markers of atherosclerosis. There was linear trend for the increase of VWF, carotid IMT (p < 0.001) and microalbuminuria (p = 0.018). The association between VEF and both markers remained statistically significant after adjusting for cardiovascular risk factors and inflammatory markers (p < 0.01). In conclusion, VWF was independently associated with both structural and functional surrogates of atherosclerosis in asymptomatic subjects, thus representing a systemic biomarker of subclinical atherosclerosis.

BACKGROUND AND OBJECTIVES: Fibrinogen has been found to be an independent risk factor for cardiovascular disease. The aim of this study was to validate the measurement of plasma fibrinogen as a marker of subclinical atherosclerosis in a series of asymptomatic subjects (n=519, median age 55.5 years, 80% men). DESIGN AND METHODS: All individuals had a complete clinical examination, lipid profile (cholesterol and its high and low density lipoprotein fractions and triglycerides), global vascular risk assessment (PROCAM), and B-mode ultrasonography of the carotid arteries to determine the intima-media thickness (IMT) and the presence of atheroma plaques. C-reactive protein (CRP), and von Willebrand factor (vWF) were also measured in all subjects as markers of inflammation/endothelial damage. RESULTS: In the univariate model, a positive relationship was found between plasma fibrinogen concentration and carotid IMT (p