Medicine (St Vincent's) - Theses
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ItemCoronary microcirculatory function in patients with ischaemic heart disease: a focus on novel assessment, management and outcomes of coronary microcirculatory function( 2015)Although there have been improvements in pharmacotherapy and percutaneous coronary intervention, patients with ischaemic heart disease, still pose a significant health burden. It has become increasingly evident that cardiovascular outcomes are impacted upon by dysfunction of the coronary microvasculature. Novel direct invasive measures, such as the index of microcirculatory resistance (IMR), have recently been developed. This index of microvascular function has been shown to have significant clinical utility in patients with ischaemic heart disease. However, to date, the body of knowledge on the state of the microcirculation as assessed by IMR in subsets of patients, such as thrombolysed ST-segment elevation myocardial infarction (STEMI) and Non-ST segment elevation myocardial infarction (NSTEMI), is lacking. Furthermore, in patients with NSTEMI, the effect of targeted therapies on IMR and hence microvascular function, is unknown. Finally, no test is perfect and the development of supplementary invasive measures of microvascular function may improve the management of patients with ischaemic heart disease and further enhance our understanding of microvascular dysfunction. The aim of this thesis was to examine microvascular function in patients with ischaemic heart disease. Specifically, I will examine and compare microvascular function, as assessed in particular by IMR, in patients presenting with thrombolysed ST-segment elevation myocardial infarction undergoing a pharmacoinvasive strategy and non-ST segment elevation myocardial infarction. I will examine the relationship between measures of microvascular function, including the IMR, and left ventricular recovery in patients presenting with ST-segment elevation myocardial infarction and undergoing a pharmacoinvasive strategy. I will also examine microvascular function, as assessed by IMR, and the role of the antiplatelet agent, abciximab, in patients presenting with Non-ST segment elevation myocardial infarction. Finally, I will examine and evaluate a novel measure of microvascular function, the coronary artery augmentation index, in patients with stable angina undergoing percutaneous coronary intervention. A full representation of patients with ischaemic heart disease undergoing percutaneous coronary intervention (PCI) were studied; 31 patients with STEMI, 36 patients with NSTEMI and 40 patients with stable angina. Invasive coronary physiological measurements in the culprit vessel were taken during the index procedure at varying times depending on the study protocol. Left ventricular function was assessed by either transthoracic echocardiography or cardiac MRI and compared with measures of microvascular function. Cardiac biomarker levels were taken pre-procedure, at the time of procedure and post procedure for up to 24 hours post intervention. In summary, the main findings of this thesis are: • Invasive measures of microvascular function, such as IMR, are significantly higher in a pharmacoinvasive STEMI population than in a clinically stable NSTEMI population. • In a STEMI population undergoing a pharmacoinvasive strategy, in contrast to other traditional markers of microvascular dysfunction, post PCI IMR correlates with left ventricular function and has the potential to predict left ventricular recovery at three months post STEMI. • In patients with NSTEMI undergoing PCI, a bolus dose of intracoronary abciximab improves coronary microvascular function as assessed by IMR. • Coronary augmentation index is a valid and reproducible measure of microvascular function in patients with stable angina undergoing PCI. • Coronary augmentation index is a predictor of periprocedural myocardial injury and may be able to identify those patients who are at greater risk of such injury following intervention. The findings of this Doctor of Medical Science are novel and have important clinical implications for the clinician. The work in this thesis supports the notion that it is important to consider microvascular dysfunction in patients with ischaemic heart disease undergoing PCI. With accurate assessment and appropriate management clinical outcomes may be improved. The work presented does warrant further investigation in larger multicentre trials. I anticipate that these will support the findings of this thesis and by measuring microvascular function will can aid risk-stratification and enable a more intensive therapeutic strategy not only within the catheterisation laboratory, but post procedure in the short and medium term.
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ItemChronic hepatitis B in an Australian tertiary hospital cohort: natural history of disease and the association of viral markers with histological and serological outcomes( 2015)Chronic Hepatitis B (CHB) is a major worldwide public health problem with an estimated 240 million people chronically infected and at risk of the complications of liver cirrhosis and hepatocellular carcinoma. There are recognized phases of disease in CHB which are usually defined using a combination of HBeAg status, HBV DNA level and ALT level. These can provide a useful framework to conceptualise a patient’s risk of fibrosis and need for treatment. Using the large CHB cohort at our tertiary hospital in Melbourne, we described our patient group in terms of their phase of disease in a cross-sectional analysis in chapter 3. This analysis highlighted some of the limitations of tests used, eg the insensitivity of older generation HBV DNA. Histological liver injury due to hepatitis B virus (HBV) was also able to be examined in a large proportion of our cohort with liver biopsies and in chapter 4 we evaluated the effect of HBV DNA on liver fibrosis. We found that increasing HBV DNA was associated with increasing prevalence of significant fibrosis in HBeAg negative patients, however in HBeAg positive patients, the reverse was true. This once again leads back to the concept of phase of disease in which HBeAg positive patients in the immune tolerant phase have normal ALT and minimal fibrosis despite very high HBV DNA levels. Longitudinal analysis of untreated HBeAg negative patients in chapter 5 brought to light some of the weaknesses of current classification systems for phase of disease, since we showed that low level fluxes in viral load in HBeAg negative patients were common and strict thresholds for HBV DNA to define the immune control phase were often crossed. The effects of HBV genotype and viral variants (precore and basal core promoter) on liver histology were examined in chapter 6. No significant associations were found although there was a trend towards higher prevalence of significant fibrosis in patients with HBV genotype C. Furthermore we explored the role of the novel markers of quantitative HBeAg and HBsAg (qHBeAg and qHBsAg) for classification of patients into phases in the natural history of CHB and found significant differences in qHBsAg levels in patients in different phases of disease in chapter 7. Finally we evaluated the role of qHBeAg and qHBsAg in the setting of Nucleos(t)ide analogue treatment by comparing 2 groups of HBeAg positive patients, one of which was known to lose HBeAg during the 18 months of followup and the other group which did not. Differences in both baseline and on treatment levels of qHBeAg were found between the 2 groups, however no significant differences in qHBsAg levels were noted. Management of CHB frequently involves monitoring patients to decide on the need and optimal time for therapy. A better understanding of the tools used in evaluating patients and the performance of these in different phases of disease and on therapy helps to enhance the clinical care of CHB patients.