Medicine (St Vincent's) - Theses
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ItemIdentification of structural heart disease in a high risk, asymptomatic community cohort - the SCREEN-HF Study( 2015)The development of symptomatic heart failure portends a poor prognosis, even in the current era where many effective heart failure therapies are available. Identification of subjects at particularly elevated risk of heart failure, including those with classic heart failure risk factors or underlying structural heart disease, could facilitate a more preventative approach to this condition. However, effective risk stratification tools have not yet been developed and the potential role of screening tools such as clinical risk prediction models and cardiac biomarkers requires further evaluation. The SCReening Evaluation for the Evolution of New Heart Failure (SCREEN-HF) study was designed to determine whether serum N-terminal B-type natriuretic peptide (NT-proBNP), a cardiac biomarker associated with increases in myocardial wall stress, could be used as an effective risk stratification tool in an older, asymptomatic community cohort selected by heart failure risk factors. The initial cross-sectional component of the study, with which this thesis is concerned, was developed to assess the ability of serum NT-proBNP to predict the presence of significant structural heart disease associated with an elevated risk of incident heart failure. However, longitudinal follow up in of the SCREEN-HF cohort will later assess whether serum NT-proBNP levels are effective in predicting the onset of symptomatic heart failure and other cardiovascular events. Structural heart disease was found to be common within the high risk SCREEN-HF cohort, with significant echocardiographic abnormalities detected in approximately one in four subjects. Serum NT-proBNP quintile was associated with structural heart disease, particularly left ventricular systolic dysfunction with a reduced ejection fraction. However the poor test performance characteristics of serum NT-proBNP, even at optimized cut-points, suggest that it would be an inadequate tool for detecting structural heart disease in this population, resulting in an unacceptably high number of missed cases of structural heart disease. The poor predictive capacity of serum NT-proBNP for structural heart disease in the SCREEN-HF cohort may relate to an increased noise-to-signal ratio in the setting of low absolute serum NT-proBNP values, and also to the narrower spectrum of cardiovascular risk in a population selected by heart failure risk factors. In contrast, transthoracic echocardiography was able to detect clinically significant structural heart disease in a quarter of subjects in this selected population. The high prevalence of echocardiographic abnormalities, associated with an increased risk of incident heart failure, suggests that echocardiographic screening, though more expensive and resource-intensive than measurement of serum NT-proBNP levels, may be justified in a similarly selected, high-risk population.
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ItemNovel biomarkers in the early detection of pulmonary arterial hypertension in systemic sclerosis( 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.