Medicine (St Vincent's) - Theses

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    Advanced characterisation of pulmonary hypertension: Assessment of right ventricular diastolic function and pulmonary artery wave reflection
    Murch, Stuart David ( 2016)
    Pulmonary hypertension is the net haemodynamic consequence of a wide variety of underlying pathologies. As disease progresses, right ventricular systolic dysfunction may develop. However, by the time this occurs, prognosis is poor. Like the situation in the left ventricle, chronically increased right ventricular afterload first leads to right ventricular hypertrophy and hypothetically, diastolic dysfunction. Although there is some evidence from animal models for this, human data is limited. Theoretically, the identification of right ventricular diastolic dysfunction may assist in the earlier diagnosis of pulmonary hypertension. This thesis provides evidence that right ventricular diastolic dysfunction does exist in the setting of pulmonary hypertension, that it occurs earlier than systolic dysfunction, and that it can be identified by invasive pressure measurement in the right ventricular cavity. Although echocardiography provides a useful way to assess left ventricular diastolic function, data presented here will show that currently available echocardiographic measurement of right ventricular diastolic function may not be sensitive enough to detect abnormal function. The secondary hypothesis tested is that a pressure/time analysis of pulmonary wave reflection can provide additional information in the assessment of patients with pulmonary hypertension. Data suggests that a metric of wave reflection, the pulmonary augmentation index, is closely associated with standard measures of right ventricular afterload, and therefore may not add value. However, the time to wave reflection is related to the site of obstruction in the pulmonary circulation and could theoretically assist in identifying disease aetiology.
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    Novel biomarkers in the early detection of pulmonary arterial hypertension in systemic sclerosis
    Thakkar, Vivek Pramodchandra ( 2013)
    Systemic sclerosis (SSc) is a complex disease characterised by extensive fibrosis, vascular abnormalities and autoantibodies. Pulmonary arterial hypertension (PAH) is a major cause of morbidity and mortality in SSc, and the early detection of PAH has emerged as an essential component of disease management. The hypothesis for this thesis is that biomarkers, either alone or in combination with other non-invasive screening investigations, may improve screening in patients with SSc-PAH. In this way, it may be possible to shift the burden of routine screening away from echocardiography. To begin, I present a comprehensive review of SSc-PAH focusing on the rationale and methods used to facilitate the early detection of SSc-PAH. Next, I present a systematic review highlighting some of the limitations in current screening practices, demonstrating the clinical need to further evaluate and refine current screening before making recommendations regarding the nature and frequency of screening. I then evaluate the screening utility of N-terminal-pro brain natriuretic peptide (NT-proBNP) in SSc-PAH, first proposing, and later validating a novel screening strategy combining NT-proBNP with pulmonary function tests (PFT) in a high-risk group of patients for SSc-PAH. Using this strategy, only patients who screen ‘positive’ to the proposed screening algorithm undergo echocardiography and further confirmatory testing for PAH. I show that asymmetric dimethylarginine, a novel biomarker of endothelial dysfunction involved in nitric oxide metabolism, may be an important screening and diagnostic biomarker for SSc-PAH, especially when combined with NT-proBNP. I also evaluate various other cytokines, chemokines and growth factors, previously suggested to play a role in SSc-PAH, and show in a well-characterised population of SSc-PAH patients that serum levels of interleukin-6 (IL-6), interleukin-13 (IL-13), vascular endothelial growth factor (VEGF), platelet derived growth factor (PDGF), fibroblast growth factor (FGF), fractalkine (FKN), intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) are not specific biomarkers of SSc-PAH. However, VEGF and ICAM-1 levels appeared to correlate with markers of PAH severity and deserve further study. I showed the wide variability of measured levels of these cytokines, chemokines and growth factors in SSc patients, possibly reflecting the heterogeneity of this complex disease. Overall, I demonstrate that biomarkers, particularly when combined with other non-invasive screening investigations such as PFT, may identify patients with SSc-PAH.