With current needs to better understand the interaction between atrial tissue microstructure and atrial fibrillation dynamics, micrometer scale imaging with optical coherence tomography has significant potential to provide further insight on arrhythmia mechanisms and improve treatment guidance. However, optical coherence tomography imaging of cardiac tissue in humans is largely unexplored, and the ability of optical coherence tomography to identify the structural substrate of atrial fibrillation has not yet been investigated. Therefore, the objective of this thesis was to develop an optical coherence tomography imaging atlas of the human heart, study the utility of optical coherence tomography in providing useful features of human left atrial tissues, and develop a framework for optical coherence tomography-informed cardiac modeling that could be used to probe dynamics between electrophysiology and tissue structure. Human left atrial tissues were comprehensively imaged by optical coherence tomography for the first time, providing an imaging atlas that can guide identification of left atrial tissue features from optical coherence tomography imaging. Optical coherence tomography image features corresponding to myofiber and collagen fiber orientation, adipose tissue, endocardial thickness and composition, and venous media were established. Varying collagen fiber distributions in the myocardial sleeves were identified within the pulmonary veins. A scheme for mapping optical coherence tomography data of dissected left atrial tissues to a three-dimensional, anatomical model of the human left atrium was also developed, enabling the mapping of distributions of imaged adipose tissue and fiber orientation to the whole left atrial geometry. These results inform future applications of structural substrate mapping in the human left atrium using optical coherence tomography-integrated catheters, as well as potential directions of ex vivo optical coherence tomography atrial imaging studies. Additionally, we developed a workflow for creating optical mapping models of atrial tissue as informed by optical coherence tomography. Tissue geometry, fiber orientation, ablation lesion geometry, and heterogeneous tissue types were extracted from optical coherence tomography images and incorporated into tissue-specific meshes. Electrophysiological propagation was simulated and combined with photon scattering simulations to evaluate the influence of tissue-specific structure on electrical and optical mapping signals. Through tissue-specific modeling of myofiber orientation, ablation lesions, and heterogeneous tissue types, the influence of myofiber orientation on transmural activation, the relationship between fluorescent signals and lesion geometry, and the blurring of optical mapping signals in the presence of heterogeneous tissue types were investigated. By providing a comprehensive optical coherence tomography image database of the human left atrium and a workflow for developing optical coherence tomography-informed cardiac tissue models, this work establishes the foundation for utilizing optical coherence tomography to improve the structural substrate characterization of atrial fibrillation. Future developments include analysis of optical coherence tomography imaged tissue structure with respect to clinical presentation, development of automated processing to better leverage the large amount of imaging data, enhancements and validation of the modeling scheme, and in vivo evaluation of the left atrial structural substrate through optical coherence tomography-integrated catheters

The purpose of this dissertation series was to describe sedentary behavior and its associations with cardiovascular disease (CVD) biomarkers and outcomes, and to explore the potential that reducing sedentary behavior may be a secondary prevention target for Acute Coronary Syndrome (ACS) survivors. As such, the following series of research studies evaluate the mechanisms, patterns, and correlates of sedentary behavior in relation to CVD risk and examine whether sedentary behavior might be a risk factor for CVD outcomes among ACS survivors. In Chapter II, a cross-sectional study of young, healthy adults examined a set of biomarkers representing several aspects of endothelial cell health to elucidate the relationship between free-living, habitual sedentary time and endothelial dysfunction. Results showed that there were no differences in measures of endothelial cell injury, endothelial cell reparative capacity, or upper extremity endothelium-dependent vasodilatation in participants with high compared with low volumes of device-measured sedentary behavior in a sample of young, healthy adults. These findings suggest that physiological mechanisms other than endothelial dysfunction may need to be explored as a potential link between habitual prolonged sedentary time and CVD in young adults. Chapter III employed group-based trajectory modeling to identify distinct patterns of sedentary behavior, as measured by accelerometry, in ACS survivors over the 28 consecutive days following hospital discharge, and, secondly, to explore potential correlates of these patterns. Results demonstrated that ACS patients as a group engaged in high volumes of accelerometer-measured sedentary time. Three patterns of sedentary behavior over the first month post-discharge were identified; these involved either gradual or rapid reductions in sedentary behavior. Several measures of disease severity and physical health (e.g., GRACE CVD risk score, physical health-related quality of life), and partner status (i.e., married or partnered or without partner), were associated with the worst patterns of sedentary behavior (i.e., high volume of sedentary time with only a slight decline over time). These findings provide insight on the different patterns of sedentary behavior that emerge as patients resume their daily life over the first month post hospital discharge. Chapter IV, building upon the study presented in Chapter III, examined whether accelerometer-measured sedentary behavior of ACS survivors over the first month post hospital discharge was associated with 1-year health outcomes. The purpose of this study was to understand whether sedentary behavior in the early post hospital discharge period may be an important risk factor in ACS survivors, that might be targeted in secondary prevention strategies. Results demonstrated that the average sedentary behavior over the first month post hospital discharge was not significantly associated with increased risk of 1-year recurrent major adverse cardiovascular events or hospitalizations. These findings do not support sedentary behavior in the early post hospital discharge period as a prognostic risk factor that should be modified in ACS survivors as part of secondary heart disease prevention strategy. However, studies with larger sample sizes, and that evaluate sedentary behavior patterns beyond the first month are needed. Collectively, these studies show that high volumes of sedentary behavior are prevalent in ACS survivors over the first month immediately following hospital discharge. Future work is needed to further study the underlying mechanisms through which sedentary behavior may confer CVD risk and to determine whether sedentary behavior is an important modifiable risk factor in ACS survivors.

Acute coronary syndrome (ACS), the acute manifestation of coronary heart disease (CHD), is the leading cardiovascular cause of mortality and morbidity globally, and represents one of the most common causes of acute medical admissions to Australian hospitals. Following medical and/or surgical management of ACS, lifestyle modification to reduce the underlying risk factors that contribute to the progression of the disease remains vital. Cardiac rehabilitation (CR) has been widely accepted as an intervention that can reduce mortality and modify risk factors for subsequent coronary events and cardiovascular disease. While the benefits of cardiac rehabilitation programs have been demonstrated, participation and adherence to these programs remain low for various reasons, particularly among patients whose treatment includes revascularisation with percutaneous coronary intervention. This method of revascularisation has become increasingly common due its immediate success, rapid procedural technique, short hospital stay and early return to work for patients of working age. The aim of this study was to develop and test the feasibility of an evidence-based health-related lifestyle management program for risk factor modification in patients with ACS undergoing percutaneous coronary intervention. Four distinct yet interrelated studies were undertaken as part of the Development and evaluation of a Health-related Lifestyle self-Management (HeLM) intervention for patients with ACS Project. Three of these studies informed the development of the HeLM intervention, which was based on the principles of chronic disease self-management and evidence-based practice that included best evidence from the literature, clinical expertise and patient preferences. The first study was a systematic review of the literature to identify the best available evidence of the effect of brief interventions for lifestyle modification in patients with CHD. Findings from the 17 trials included in the systematic review, although inconclusive suggest that brief structured interventions can have beneficial effects on risk factor modification and consequently on progression of CHD. The second study was a qualitative interview of CR coordinators to identify from their clinical expertise the influence of the Reducing Risk in Heart Disease guidelines on practice: the Implementation of the Cardiac Evidence-Based Reducing Risk in Heart Disease Guidelines (ICEBRG) study. Findings from this study indicated limited implementation of the guidelines due to various barriers relating to health services, CR programs, professional practice and the patient and their families. Despite these barriers, it was evident that CR coordinators were striving to overcome these odds and provide evidence-based care. The third study undertaken to identify patient preferences for CR was the Follow-up After percutaneous Coronary Treatment (FACT) Study. The findings indicated that although the majority of the participants had two or more risk factors, they lacked knowledge of the link between risk factors and CHD, and less than a third had attended CR. The main reasons for nonattendance included timing, distance to travel, length of program, work commitments and lack of motivation to attend the programs. Their suggestions for improvement included telephone follow-up and flexibility of the CR programs. This study also informed the development of a tool that can be used by clinicians to flag patients who are unlikely to attend traditional CR. Identification of these people will allow alternate strategies to reduce risk factors to be tailored to their needs. The findings from these three studies were used to develop the HeLM intervention. The final study was undertaken to assess the feasibility of the HeLM intervention that was based on evidence compared to standard treatment for promoting lifestyle modification. This study was undertaken in 51 participants who were followed up two weeks following the completion of the intervention. The findings demonstrated that patients found the information beneficial and were pleased to receive it in their homes. The telephone support was also extremely well received. The study enabled the program and the process for implementation to be refined and indicated that a large multicentre trial would be feasible. The HeLM may be a strategy that could reach patients who have thus far eluded traditional CR programs and support them to make the necessary lifestyle changes. It may also be an adjunct to traditional CR and have a synergistic effect in facilitating health-promoting behaviours in CHD patients. Studies of interventions for risk factor modification in participants with CHD require longer term follow-up to assess the effect of the intervention in the sustainability of behaviour modification. Further research is necessary to evaluate the long-term effects as well as the cost effectiveness of the intervention. / Doctor of Philosophy (PhD)

Heart failure is a cause of significant burden to both individuals and society. Individuals live with a disease where there is a decline in physical functioning, the experience of a range of symptoms including breathlessness and pain, frequent hospitalisations and death. The frequent hospital admissions that are usually precipitated by shortness of breath places an economic burden on the current health system. This burden of heart failure is expected to increase in the coming years due to factors such as the ageing population and improved survival from acute cardiac events. This current and predicted continuing burden has been recognised by the health system and has resulted in significant improvement in the pharmacotherapy and nonpharmacotherapy treatment of heart failure. Despite this improvement and with the exception of those few who receive cardiac transplantation, there is no cure for heart failure. Whist the advances in therapy have promoted significant improvements in heart failure management, symptoms including breathlessness (dyspnoea) remain a major issue. The Management of Dyspnoea in Advanced Heart Failure project explored and assessed the current therapeutic management of dyspnoea in advanced heart failure and examined two potential therapeutic options namely nebulised frusemide and long-term oxygen therapy. Following a comprehensive review of the nebulised frusemide literature, The Haemodynamic Effects of Nebulised Frusemide in Heart Failure study showed that nebulised frusemide did have an impact on the haemodynamic parameters of participants. Whilst many consider oxygen therapy as a common sense approach for breathlessness, the lack of scientific evidence for its use in chronic breathlessness with people who have normal or mildly low oxygen levels has prevented funding to supply oxygen therapy to this group of patients. The O2 Breathe Study is a palliative care study that is testing long-term home oxygen therapy versus medical air in patients who do meet the current funding arrangements. The analysis of the screening data showed that the symptom burden as a result of dyspnoea is similar to that seen in cancer and respiratory patients, and heart failure patients had lower levels of physical functioning than the respiratory group. Whilst the design of the studies in this thesis will not allow conclusions to be made regarding their efficacy for dyspnoea management in heart failure, they have provided preliminary data and hypotheses to be tested in the future. / Doctor of Philosophy (PhD)

Congenital heart disease is the most common form of birth defect, affecting approximately 1% of liveborn babies. Secundum atrial septal defect (ASD) is the second most common form of congenital heart disease (CHD). Most cases have no known cause. Chromosomal, syndromal and teratogenic causes account for a minority of cases. The hypothesis that mutations in the ASD genes NKX2-5 and GATA4 may cause apparently sporadic ASD was tested by sequencing them in unrelated probands with ASD. In this study, 1/102 individuals with ASD had an NKX2-5 mutation, and 1/129 had a deletion of the GATA4 gene. The cardiac transcription factor TBX20 interacts with other ASD genes but had not previously been associated with human disease. Of 352 individuals with CHD, including 175 with ASD, 2 individuals, each with a family history of CHD, had pathogenic mutations in TBX20. Phenotypes included ASD, VSD, valvular abnormalities and dilated cardiomyopathy. These studies of NKX2-5, GATA4 and TBX20 indicate that dominant ASD genes account for a small minority of cases of ASD, and emphasize the considerable genetic heterogeneity in dominant ASD (also caused by mutations in MYH6 and ACTC). A new syndrome of dominant ASD and the Marcus Gunn jaw winking phenomenon is reported. Linkage to known loci was excluded, extending this heterogeneity, but a whole genome scan did not identify a candidate locus for this disorder. Previous studies of inbred laboratory mice showed an association between patent foramen ovale (PFO) and measures of atrial septal morphology, particularly septum primum length (???flap valve length??? or FVL). In humans, PFO is associated with cryptogenic stroke and migraine, and is regarded as being in a pathological contiuum with ASD. Twelve inbred strains, including 129T2/SvEms and QSi5, were studied, with generation of [129T2/SvEms x QSi5] F1, F2 and F14 mice. Studies of atrial morphology in 3017 mice confirmed the relationship between FVL and PFO but revealed considerable complexity. An F2 mapping study identified 7 significant and 6 suggestive quantitative trait loci (QTL), affecting FVL and two other traits, foramen ovale width (FOW) and crescent width (CRW). Binary analysis of PFO supported four of these.

Bibliography: leaves 97-112. / vii, 112 leaves : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Physiology, 2003

Thesis (Ph. D.)--University of Hong Kong, 2006. / Title proper from title frame. Also available in printed format.

Thesis (Ph. D.)--University of Hong Kong, 2007. / Title proper from title frame. Also available in printed format.

Abdominal obesity is a part of insulin resistance syndrome that is closely linked to increased risk of coronary artery disease (CAD). Because fat tissue acts as an endocrine target and source of hormone production, increased metabolism or production of chemical messengers in fat tissue may result in metabolic perturbations that contribute to occurrence and recurrence of coronary events. This dissertation research entails two separate approaches. The first study, a cross-sectional analysis, sought to determine whether serum cortisol responses to oral glucose loading are associated with abdominal obesity, non-esterified fatty acid (NEFA) suppression, and self-reported symptoms of depression in 26 non-diabetic coronary patients. We conclude that lower cortisol responses to oral glucose loading are associated with abdominal obesity, reduced NEFA suppression, and fewer symptoms of depression (P���0.028). Future prospective studies should determine whether psychosocial risk factors, such as depression and anxiety, increase cortisol production, whether increases in cortisol production act synergistically with a positive energy balance in the development of abdominal obesity, and whether increases in abdominal obesity lead to increases in cortisol metabolism and insulin resistance. C-reactive protein (CRP) is a marker of low-grade inflammation that is associated with increased risk for recurrent events in coronary patients. Fat tissue also secretes proinflammatory cytokines that stimulate hepatic production of CRP. Thus, the second study, an intervention study, sought to determine whether the first three months of cardiac rehabilitation could reduce serum concentrations of CRP and the proinflammatory cytokine, tumor necrosis factor-�� (TNF-��), in our non-diabetic coronary patients (N=26). Results from the intervention study showed significant reductions in serum CRP levels (P=0.012) that were associated with reductions in waist circumferences after cardiac rehabilitation (r=0.39, P=0.049). However, changes in serum TNF-�� levels after cardiac rehabilitation were nonsignificant (P=0.869). Thus, we conclude that cardiac rehabilitation may reduce the severity of low-grade inflammatory conditions, in part, through reductions in waist circumference in non-diabetic coronary patients. / Graduation date: 2001

Cardiotoxicity associated with many cancer drugs is a critical issue facing physicians these days and a huge hurdle that must be overcome for a side effects-free cancer therapy. Survival of cardiac myocytes is compromised upon the exposure to certain chemotherapeutic drugs. Unfortunately, the mechanisms implicated in cardiac toxicity and the pathways governing myocyte survival are poorly understood. The following thesis addresses the mechanisms underlying the cardiotoxicity of two anticancer drugs, doxorubicin (DOX) and Imatinib mesylate (Gleevec). Transcription factor GATA-4, has recently emerged as an indispensable factor in the adult heart adaptive response and cardiomyocyte survival. Therefore, the specific aim of this project was to determine the role of GATA-4, its upstream regulators, as well as partners in survival. A combination of cell and molecular techniques done on in vivo, and ex vivo models were utilized to tackle these issues. In this study, we confirmed the cardiotoxicity of the anticancer drug, Imatinib mesylate and found to be age dependent. GATA-4, already known to be implicated in DOX-induced toxicity, was confirmed as an Imatinib target. At the molecular level, we identified IGF-1 and AKT as upstream regulators of GATA-4. Moreover, we confirmed ZFP260 (PEX-1), a key regulator of the cardiac hypertrophic response, as a GATA-4 collaborator in common prosurvival pathways. Collectively, these results provide new insights on the mechanisms underlying drug-induced cardiotoxicity and raise the exciting possibility that cancer drugs are negatively affecting the same prosurvival pathway(s), in which GATA-4 is a critical component. Therapeutic interventions aimed at enhancing GATA-4 activity may be interesting to consider in the context of treatments with anticancer drugs.