This experiment tested three hypotheses linking the right cerebral regulation of hostility and physiological arousal. First, replication of previous research supporting heightened physiological (systolic blood pressure, diastolic blood pressure, and heart rate) reactivity among high hostile subjects was attempted. Second, a positive association between hostility and reactivity of facial valence and intensity to stress were expected. Last, hemispheric lateralization of cerebral activity in response to stress was measured. Low- and high-hostile subjects were identified using the Cook Medley Hostility Scale (CMHS). All subjects completed the cold pressor paradigm and were videotaped before, during, and after the stressor for analysis of facial valence and intensity. Physiological measures (SBP, DBP, and HR) were recorded and dichotic listening procedures were administered before and after the stressor. The primary finding of this research was greater right cerebral activation to stress among high-hostile subjects, as indicated by their enhanced intention to the left ear. Data further supported previous findings of heightened physiological reactivity to stress among high-hostiles. However, no hostility group differences on facial expression measures were found. Data suggest a positive relationship between right cerebral activity and cardiovascular arousal. / Master of Science

No / Cardiovascular disease is the principal cause of death in patients with type 2 diabetes (T2DM). Exposure of the vasculature to metabolic disturbances leaves a persistent imprint on vascular walls, and specifically on smooth muscle cells (SMC) that favours their dysfunction and potentially underlies macrovascular complications of T2DM. Current diabetes therapies and continued development of newer treatments has led to the ability to achieve more efficient glycaemic control. There is also some evidence to suggest that some of these treatments may exert favourable pleiotropic effects, some of which may be at the level of SMC. However, emerging interest in epigenetic markers as determinants of vascular disease, and a putative link with diabetes, opens the possibility for new avenues to develop robust and specific new therapies. These will likely need to target cell-specific epigenetic changes such as effectors of DNA histone modifications that promote or inhibit gene transcription, and/or microRNAs capable of regulating entire cellular pathways through target gene repression. The growing epidemic of T2DM worldwide, and its attendant cardiovascular mortality, dictates a need for novel therapies and personalised approaches to ameliorate vascular complications in this vulnerable population.

The purpose of this study is to develop a test method to non-invasively measure the development of subclinical atherosclerosis through acoustic sound wave analysis. This test method involves the manufacturing and use of silicone arteries with varying relative roughness values in their inner diameters to mimic arterial plaque buildup, a flow model, and a physiological microphone. A flow model that can generate both steady and oscillatory flow to mimic the pulsatile flow of a heartbeat was developed to successfully test and analyze fluid flow through the varying arteries. The first finding in this study was that confocal microscopy is an effective method is quantifying the surface roughness of the inner diameter the silicone artery phantoms. Results of this study found that the surface roughness of the arteries reflects the increase of surface roughness hypothesized when manufacturing the artery molds. The gravitational flow model experimental design proved to be effective in collecting steady flow data that was used to verify the experimental relative roughness and friction factor values. Additionally, the results indicated that pressure drop and friction factor (both experimental and theoretical) increased as the surface roughness of the artery increased. Furthermore, the pulsatile flow model was unsuccessful in generating a consistent frequency that was greater than 2.0 Hz. Because of this, many of the Womersley’s numbers remained undefined or frequency dependent. No concrete conclusions can be drawn regarding the relationship between Womersley’s number and surface roughness during pulsatile flow. A key finding in this study was that the signal power of an FFT of the audio data vs. relative roughness for both steady and pulsatile flow conditions experienced a slightly positive linear association. Meaning that there could be a relationship between the increase of surface roughness and the increase of signal power in an FFT of the audio data. Based on the findings in this study, this demonstrates that there could be a method to correlate the values of signal power to a specific relative roughness value.

Elevated postprandial triacylglycerol concentrations ([TAG]) are associated with the development and progression of atherosclerosis, and are established as an independent risk factor for future cardiovascular disease. Considering the majority of the daytime is spent in a postprandial state typically, and the paediatric origins of atherosclerosis are well established, lifestyle interventions including manipulations of exercise energy expenditure and dietary energy intake should be initiated early in life. Therefore, this thesis aimed to investigate the postprandial metabolic responses to different exercise and energy intake manipulations in boys and girls, with concentrations of circulating TAG representing the primary outcome of interest. To achieve this, a total of 60 healthy 11 to 13 year old boys and girls were recruited into five experimental studies. The first experimental study (Chapter 4) demonstrated that a single session of high-intensity interval running (HIIR) involving 10 x 1 min intervals at 100% maximal aerobic speed (MAS) resulted in a moderate reduction in postprandial plasma [TAG] in 11 to 12 year old boys. In the second experimental study (Chapter 5), immediate replacement of the moderate-intensity exercise-induced energy deficit negated the reduction in postprandial plasma [TAG] in 11 to 13 year old boys. Furthermore, an exercise-induced energy deficit was required to promote an increase in whole-body fat oxidation. The importance of the associated energy deficit was explored further in Chapter 6, which demonstrated that a moderate-intensity exercise-induced energy deficit elicited a greater reduction in postprandial plasma [TAG] than an isoenergetic diet-induced energy deficit in 11 to 13 year old girls (21% vs. 10% respectively). Chapter 7 compared the effect of 10 x 1 min interval runs at 100% MAS (HIIR) and 5 x 1 min interval runs at 100% MAS combined with a mild reduction in habitual energy intake by 0.82 MJ (195 kcal; HIIR-ER) on postprandial metabolism in 11 to 13 year old girls. Acute manipulations of low volume HIIR and ER reduced postprandial plasma [TAG] and increased resting whole-body fat oxidation, with the magnitude of effect marginally, although not meaningfully, greater following HIIR than HIIR-ER. The final experimental chapter (Chapter 8) compared directly healthy 11 to 13 year old boys and girls postprandial TAG responses to acute HIIR. Although postprandial plasma [TAG] was substantially lower in boys compared with girls, the magnitude of reduction following HIIR was similar between the sexes (11% vs. 10% respectively). Collectively, these studies demonstrate the efficacy of acute moderate- and high-intensity exercise, and to a lesser extent energy-intake restriction, to reduce postprandial plasma [TAG] and increase resting whole-body fat oxidation in boys and girls. Furthermore, the beneficial effect of exercise on postprandial metabolism appears dependent on the maintenance of the associated energy deficit. These lifestyle interventions have the potential to provide a practical, effective and engaging stimulus to promote a healthier cardiovascular risk profile in early adolescence.

Cardiovascular disease is the leading cause of mortality in Western societies and is linked to multiple modifiable risk factors including lifestyle choices. Emerging evidence implicates exposure to persistent environmental pollutants, such as polychlorinated biphenyls (PCBs), as a risk factor for the development or progression of cardiovascular disease. To reduce disease risks, it is critical to identify sensible means of biomedically reducing the toxicity of persistent organic pollutants and related environmental stressors. First, we tested a hypothesis that endothelial cell inflammation and subsequent cardiovascular toxicity initiated by coplanar PCBs is modulated by the crosstalk between caveolae and Nuclear factor (erythroid-derived 2)-like 2(Nrf2) related proteins. Caveolae are lipid-enriched organelles found abundantly in endothelial cells and are important mediators of endocytosis and signal transduction. Caveolin-1 (Cav-1), the major structural protein of caveolae, is known to bind and concentrate multiple proteins related to cardiovascular disease and PCB toxicity. Downregulation of Cav-1 protects against PCB-induced vascular toxicity, but possible mechanisms of this defense remain elusive. Studies using endothelial cells isolated from mice deficient in Cav-1 as well as in vitro silencing assays demonstrated that loss of Cav-1 increases available antioxidant enzymes by upregulating the antioxidant master controller Nrf2. Nutritional interventions focused on diets high in bioactive food components, such as polyphenols or certain fatty acids, may prove to be effective at decreasing environmental pollutant induced diseases. To test the hypothesis that dietary intervention can sensitize Nrf2 and/or caveolae signaling pathways, leading to a more effective anti-inflammatory defense against PCB insults, mice were fed a green tea polyphenol enriched diet and challenged with coplanar PCB 126. Mice fed an enriched diet and exposed to PCBs exhibited lower levels of oxidative stress and higher levels of multiple Nrf2 target antioxidant enzymes. Also, in separate in vitro studies, pretreatment of endothelial cells with the endogenously formed nutrient metabolite, nitro-linoleic acid, altered caveolae and Nrf2 related proteins, resulting in a modified response to PCB exposure. Together, these data support the paradigm that nutritional modulation may be a sensible means of reducing disease risks associated with exposure to environmental pollutants.

Cardiovascular disease (CVD) is a major public health problem and a primary cause of morbidity and mortality in the United States. Regular physical activity is recommended for prevention and management of CVD. Despite the cardiovascular health benefits of physical activity most adults are physically inactive. Therefore, the aim of this dissertation was to examine the factors associated with adherence to physical activity among individuals with or without CVD. The first paper is a report of a study conducted to examine which baseline demographic (age, gender, marital status, socioeconomic status, and place of residency), psychosocial (social support, depression, anxiety, and fatalism), and clinical (past history of exercising, comorbidity, and health literacy) variables predicted successful adoption of the active lifestyle recommendation of increasing moderate-to-vigorous physical activity by an accumulated 15 minutes or more each day following a CVD risk reduction intervention and 2) to identify which of those same factors predicted dropout from the CVD risk reduction intervention among at-risk individuals in rural America. The study sample consisted of 399 rural Americans. The results revealed that a higher anxiety level was a predictor of active lifestyle modification following a CVD risk reduction intervention. In contrast, younger age and low health literacy were predictors of dropout from a CVD risk reduction intervention. The second paper is a literature review of studies investigating the factors that affected enrollment in cardiac rehabilitation in patients with heart failure (HF). The aims of this review were to: (a) describe enrollment rates of patients with HF in cardiac rehabilitation programs, (b) review the literature on factors affecting enrollment of patients with HF, and (c) identify areas for future research. It is difficult to draw conclusion about enrollment rates because the period of time after hospital discharge that enrollment was measured varied across studies. A wide array of demographic, psychosocial, and clinical variables have been identified as potential barriers of enrollment in cardiac rehabilitation programs. Additional research including patients with HF is needed. The third paper is a report of a cross-sectional study of 279 patients with HF. The aims were to determine 1) the amount of variance in the functional status predicted by depressive symptoms, perceived control, self-rated health, HF self-care maintenance behaviors, and serum N-terminal pro-B-type natriuretic peptide ( NT-pro-BNP) biomarker of cardiac dysfunction in patients with HF and 2) whether NT-pro-BNP mediated the relationship between self-care maintenance behaviors and functional status. Depressive symptoms, poor self-rated health, non-adherence to physical activity, and greater serum NT-pro-BNP levels were independently associated with worse perceptions of functional status. Serum NT-pro-BNP levels partially mediated the association between adherence to physical activity and perception of functional status. The findings from this dissertation provided further evidence of the importance of adherence to physical activity and identify key variables that promote participation in interventions to promote heart healthy lifestyles and adherence to physical activity.

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.

The cholesterol-lowering effect of mixed linkage (1→3) (1→4)-β-D-glucans (β-glucan) from barley has been documented, yet the underlying mechanism responsible for this action and factors influencing it, such as physicochemical properties of β-glucan and genetic background of an individual, remain unclear.As a component of dietary fibre, β-glucan also has the potential to shift the gut microbial community, however, whether alterations in the gut microbiota are associated with the physiological effects of β-glucan have yet to be determined. This study was designed to assess the effects of β-glucan molecular weight (MW) and dose on loweringserum cholesterol levels and to elucidate its mechanism of action in human subjects. Additionally, this study examined gene-diet interactions as well as changes in the gut microbiota profile following consumption of barley foods. In a controlled four phase crossover trial, mildly hypercholesterolemic but otherwise healthy subjects (n =30) were randomly assigned to receive breakfasts containing 3g high MW (HMW), 5g low molecular weight (LMW), 3g LMW barley β-glucan or a control diet with wheat and rice (WR control), each for 5 weeks. The washout period between the phases was 4 weeks. The consumption of 3g/d HMW diet lowered total cholesterol (TC) compared with WR control diet (P =0.0046), but not the LMW diet at either 3g/d or 5g/d. Individuals with the SNP rs3808607-G allele of CYP7A1 had greater TC reduction in response to 3g/d HMW β-glucan diet compared to the individuals carrying homozygous TT alleles (P<0.01). Cholesterol absorption and synthesis were not changed, but bile acid synthesis increased by 3g/d HMW diet compared to the control. Consuming 3g HMW/d β-glucan altered gut microbiota at the phylum and genus levels and the impacted microbial members was correlated with favorable shifts of cardiovascular disease risk factors. In conclusion, physicochemical properties of β-glucan play critical roles in the cholesterol-lowering effect and gut microbiota alteration ability of β-glucan. The results suggest the increasing bile acid synthesis rather than inhibiting cholesterol absorption and synthesis is the mechanism responsible for the cholesterol reducing property of β-glucan.The altered microbiota profile by HMW β-glucan is associated with its physiological effect. / February 2016

Lowering LDL-cholesterol with statin therapy produces substantial reductions in cardiovascular events, and larger cholesterol reductions may produce larger benefits. Rarely, myopathy occurs with statins, especially at higher doses and in combination with certain medications. Similarly strong associations might exist between myopathy with high-dose statin regimens and genetic variants, especially those affecting blood statin levels. This study aimed to find genetic variants associated with statin-induced myopathy. A feasibility study was completed to assess whether plausible effect sizes of 5 to10-fold higher risks per genetic variants could be detected among 50-100 cases with statin-induced myopathy and to consider the best study design. A genome-wide association study was then carried out using approximately 300,000 genetic markers (and additional fine-mapping) in 85 people with definite or incipient myopathy and 90 controls, who were all taking 80mg simvastatin daily in a 12,000 participant trial of 80mg vs 20mg simvastatin daily. The cases were also compared to 2,300 additional controls who had not been exposed to intensive-dose statin therapy. Replication of the myopathy result and lipid-lowering associations were tested in a 20,000 participant trial of 40mg simvastatin daily versus placebo. The genome-wide scan yielded a single strong association (p = 4x10^-9) of myopathy with the rs4363657 single nucleotide polymorphism (SNP) located within the SLCO1B1 gene on chromosome 12. This non-coding SNP was in nearly complete linkage disequilibrium (r²=0.97) with the non-synonymous rs4149056 SNP. The population prevalence of the rs4149056 C allele was 15%, and the odds ratio for myopathy was 4.5 (95% confidence interval 2.6 to 7.7) for each copy of the C allele and 16.9 (4.7 to 61.1) for CC vs TT homozygotes. Over 60% of these myopathy cases could be attributed to the C variant. The SLCO1B1 gene encodes the organic anion transport polypeptide OATP1B1, which has been shown to regulate hepatic uptake of statins. In literature reports, rs4149056 reduced statin transport and was associated with 37% (31% to 44%) higher systemic statin acid levels per C allele. The association of rs4149056 with myopathy was replicated in the trial of 40mg simvastatin daily, which also showed that it was associated with the cholesterol-lowering effects of simvastatin. No SNPs in any other region were clearly associated with myopathy (although comparison of the myopathy cases with the 2,300 controls identified a region of chromosome 1p12 that warrants further study). This study identified common variants in SLCO1B1 that influence the risks of statin-induced myopathy substantially. Genotyping these variants may be useful for tailoring both the statin dose and safety monitoring. More generally, such studies of the genetic determinants of serious adverse reactions with other drug classes may help to improve the balance between treatment efficacy and safety.

Computational modelling and simulation, in close interaction with experiments, has provided invaluable insight into the biochemical, mechanical and electrophysiological function and dysfunction of the heart. However, limitations in imaging techniques and computing resources have precluded the analysis of tissue architecture near the cellular scale and the effect of this architecture on cardiac function. It is the wider aim of this thesis to develop a framework to characterise cardiac microstructure and to investigate the role of microstructure in cardiac propagation dynamics and arrhythmogenesis. An initial modelling study elucidates the effect of blood vessels in sustaining arrhythmic episodes, and how the accurate modelling of fibre direction in the vicinity of the vessels mitigates this detrimental mechanism. A mathematical model of fibre orientation in a simple geometry around blood vessels has been developed, based on information obtained from highly detailed histological and MRI datasets. A simulation regime was chosen, guided by the vasculature extracted from whole heart MRI images, to analyse ventricular wavefront propagation for different orientations and positions of blood vessels. Our results demonstrate not only that the presence of the blood vessels encourages curvature in the activation wavefront around the blood vessels, but further that vessels act to restrict and prolong phase singularities. When compared to a more simplistic implementation of fibre orientation, the model is shown to weaken wavefront curvature and reduce phase singularity anchoring. Having established the importance of microstructural detail in computational models, it seems expedient to generate accurate data in this regard. An automated registration toolchain is developed to reconstruct histological slices based on coherent block face volumes, in order to present the first 3-D sub-cellular resolution images of cardiac tissue. Although mesoscopic geometry is faithfully reproduced throughout much of the dataset, low levels of transformational noise obfuscate tissue microstructure. These distortions are all but eradicated by a novel transformational diffusion algorithm, with characteristics that outperform any previous method in the literature in this domain, with respect to robustness, conservation of geometry and extent of information transfer. Progress is made towards extracting microstructural models from the resultant histological volumes, with a view to incorporating this detail into simulations and yielding a deeper understanding of the role of microstructure in arrhythmia.