Medicine (Northwest Academic Centre) - Theses
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ItemNitric oxide in the pathogenesis of acute decompensated heart failure( 2021)Heart failure (HF) is a heterogenous syndrome broadly defined as the inability of the heart to meet the metabolic demands of the body. HF is one of the leading causes for a hospital admission in Australia and around the world, costing the Australian health care system over $2billion per annum. Patients with HF often transition between chronic HF, where signs and symptoms are minimal and paired with a relatively stable hemodynamic profile, and acute decompensated HF (ADHF), where there is a rapid worsening of symptoms and hemodynamic profile, often requiring a hospital admission. Nitric oxide (NO) is considered one of the key regulatory molecules produced in the vasculature, playing important roles in blood pressure regulation, platelet aggregation, and endothelial cell function. Given the importance of NO within the cardiovascular system, it was thought that dysregulated NO may be a key factor in the pathogenesis of ADHF. In this thesis, NO in ADHF is the linking theme between all of the presented chapters. The first investigational chapter examined NO biology, indexed by plasma nitrite (NO2-) concentrations, in patients with chronic and acute HF with a reduced ejection fraction (HFrEF). Findings from this chapter indicate that in patients with acute HFrEF have decreased NO production and bioavailability compared to their chronically compensated counterparts. Specifically, we found higher concentrations of asymmetric dimethylarginine (ADMA) and nitrotyrosine (3-NT) in patients with acute HFrEF, in an inverse proportion to the observed plasma NO2- concentrations. Following this, a similar investigation was performed in patients with chronic and acute HF with a preserved ejection fraction (HFpEF). Results from this investigation indicated that NO production and bioavailability was decreased in patients with acute HFpEF. NO biology was then examined in patients with ADHF with a concomitant acute kidney injury, a phenomenon known as cardiorenal syndrome. This investigation yielded the somewhat surprising finding that markers of worsening renal function were associated with increased NO bioavailability. The final investigational chapter explored the role of inflammation and oxidative stress and their relationship to NO in patients with chronic HF and ADHF. Along with reduced NO bioavailability, patients with ADHF displayed proportionately increased inflammatory activation (including plasma concentrations of the biomarker myeloperoxidase) and increased oxidative stress (3-NT) compared to patients with chronic HF. The results of this chapter aided in proposing a novel paradigm of decompensation, particularly in patients with HFrEF. Finally, given the results of decreased NO bioavailability, increased inflammation, and increased oxidative stress in ADHF, a short review of the current therapeutic literature was conducted. Suggestions of therapeutic strategies are also elaborated on in the final discussion chapter. This thesis presents novel and important information surrounding the biology of NO, which may be a key determinant in patients with chronic HF decompensating into ADHF.
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ItemThe management of acute decompensated heart failure in a geriatric population: evaluation of novel strategies in a contemporary hospital setting( 2020)Heart failure is a heterogeneous complex disease, with increasing prevalence in the elderly. It is a morbid disease characterized by high mortality and frequent hospital re-admissions, responsible for a significant burden to the patient and to healthcare services. This thesis will examine unique approaches to the hospital system care of acute decompensated elderly heart failure patients by two main projects. Project one is an evaluation of Western Health’s implementation of a ‘cardio-geriatric ’unit and its effect on length of stay and readmission compared to previous routine practice. This found that the intervention did not change length of stay or readmission, however uniquely described a complex group and explores reasons why it may be difficult to achieve these outcomes. Project two explores the significance of anemia and iron deficiency, and the effect on treatment of iron deficiency, a significant comorbidity in heart failure in an elderly population. It demonstrates the prevalence and patterns of iron use in this group of patients. This thesis adds to the literature an exploration of the care provided to elderly comorbid heart failure patients in the hospital setting. It demonstrates the medical complexity of this group of patients and the difficulty in curbing outcomes in this group of patients. It allows for future research to develop alternative models of care or intervention or perhaps induce a paradigm change in the approach to care for the elderly comorbid heart failure patients.
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ItemAn Examination of Heart Failure Rehospitalisation in a Western Metropolitan Melbourne Population( 2020)Heart failure is a complex clinical syndrome, associated with a significant burden of morbidity and mortality, including a high rate of rehospitalisation. Reducing the burden of rehospitalisation among patients with heart failure is a recognised priority for healthcare systems. However, in order to optimize outcomes, contemporary studies have emphasized the need for better understanding of the clinical heterogeneity of heart failure populations. Extending beyond the understanding of pathophysiological heterogeneity, the elucidation of sociodemographic factors may also reveal greater opportunities for targeted optimisation. Moreover, utilising new methods by which rehospitalisation is assessed may lead greater insights than would otherwise be captured by conventional means. This project aims to expand the understanding of rehospitalisation burden in evolving heart failure populations. It evaluates the adverse impact of cultural and linguistic diversity on rehospitalisation outcomes in patients with heart failure. A discussion of important methodological concepts into researching culturally and linguistically diverse (CALD) patient groups is carried out. In doing so, a novel operational approach to defining CALD patients is presented. This thesis also explores the measures of which rehospitalisation is evaluated in heart failure patients. It described the added value of analysing all recurrent hospital admissions (events), an approach which is very seldom performed in heart failure research. An assessment of several modelling techniques for evaluating rehospitalisation burden is performed, specifically in relation to heart failure type (i.e. heart failure with preserved vs reduced ejection fraction). In doing so, demonstrate the analysis of recurrent hospitalisations, compared to traditionally utilised first-event statistical approaches, may be a more informative and clinically relevant measure when evaluating the burden of heart failure rehospitalisation. As the prevalence of heart failure is rising and patients are becoming more diverse and complex, there is an increasing need to better characterise and understand these evolving heart failure populations. Further elucidating the heterogeneity of heart failure populations will help guide improvements to existing management approaches, as well as the direct the development of new targeted approaches.