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.