Medicine (Austin & Northern Health) - Theses
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ItemClinical risk stratification in patients with advanced liver disease and portal hypertension( 2021)Liver cirrhosis, an advanced stage of progressive hepatic fibrosis resulting from any chronic insult to the liver, is a serious medical condition that adversely affects both quality of life and life expectancy. Risk stratification represents a systematic predictive modelling process to identify patients who are at risk of poorer health outcomes and who are expected to benefit most from a particular intervention. Risk stratification in liver disease was first developed in the 1960's and has experienced a resurgence of interest with the development of new therapies for cirrhosis and the increasing accessibility of liver transplantation. The aim of this thesis is to advance the knowledge of risk stratification in patients with cirrhosis to guide clinical decision making and ultimately improve patient care. In the lifecycle of a typical patient with cirrhosis, clinical settings were identified where a paucity of literature currently exists in relation to risk stratification. These include acute variceal bleeding, the development of hepatic encephalopathy, pre-transplantation stratification of cardiac risk and post-transplantation clinical deterioration and unplanned intensive care unit readmission.
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ItemThe Role of Energy Metabolism in Renal Fibrosis( 2021)The prevalence of chronic kidney disease (CKD) is rising with significant cost and burden to our health system. Renal fibrosis is the common outcome of CKD independent of the underlying aetiologies. Changes in energy metabolism are emerging as a key contributor to renal fibrosis. Expression of genes regulating fatty acid and carbohydrate metabolism is reduced in the fibrotic kidney. Metabolic reprogramming has been reported in several models of renal disease, although its exact mechanism remains obscure. We aimed to determine the role of phosphorylation events that control fatty acid oxidation (FAO) and glycolysis in renal fibrosis. The folic acid nephropathy (FAN) and unilateral ureteric obstruction (UUO) models were induced in mice with knock-in (KI) mutations of phosphorylation sites (phosphosites) in acetyl CoA carboxylase 1 and 2 (ACC 1/2 KI mice), the major regulator of FAO, and 6-phosphofructo-2kinase/fructose-2,6-biphosphatase (PFKFB2 KI mice), the major regulator of glycolysis. Metformin, which activates 5'-AMP-activated protein kinase (AMPK) to increase phosphorylation of ACC, was administered to mice with FAN. ACC Ser79 phosphorylation was reduced in folate-treated tubular epithelial cells (p<0.01) and WT mice with FAN (p<0.05). Mutation of these sites in ACC1/2 KI mice with FAN or UUO caused lipid accumulation (Oil Red O p<0.01), increased triglyceride (p<0.01), increased collagen (PicroSirius red p<0.001; Masson’s Trichrome p<0.01; qRT-PCR p<0.01) and increased A-SMA (Western blot p<0.05; qRT-PCR p<0.01). Metformin administration was associated with reduced fibrosis (PicroSirius red p<0.01) and reduced lipid accumulation (Oil Red O p<0.05) in WT mice, but not in ACC1/2KI mice. Phosphorylation of the kidney isoform, PFKFB2, on residues Ser466 and Ser483 stimulates glycolysis. PFKFB2 KI mice have inactivating mutations at these phosphosites. Primary cultures of renal tubular epithelial cells from PFKFB2 KI mice had reduced ability to stimulate glycolysis when compared to WT cells (P<0.001). Absence of phosphorylation in PFKFB2 KI mice following UUO was associated with increased renal fibrosis (Picrosirius red p<0.001), increased fibronectin (Western blot p<0.05) and increased A-SMA (Western blot p<0.05). Fibrotic changes were less pronounced in the FAN model. These data suggest that reduced phosphorylation of ACC and PFKFB2 promote fibrosis and are deleterious following renal injury. Drugs that reverse this, such as metformin, may be useful in preventing and treating renal fibrosis. Fibrotic changes were most severe in PFKFB2 KI mice following UUO, highlighting the importance of glycolysis in the distal nephron.
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ItemNo Preview AvailableCardiovascular Disease in Patients with End-Stage Liver Disease undergoing Transplantation( 2021)It has been known for centuries that the heart and the liver are closely related. Galen suggested the body was controlled by the tripartite system of the liver, heart and brain, with the liver being the source of all veins and the principal instrument of sanguification. The complex interconnectedness of these organ systems is no more apparent than in patients with liver dysfunction. Liver cirrhosis leads to autonomic and neurohormonal dysregulation which can culminate in circulatory and cardiovascular dysfunction. These observations have been brought to the fore with advances in experimental techniques including biomarkers and structural imaging that have highlighted the manifestations of cirrhotic cardiomyopathy. However, the precise clinical consequences of these cardiac maladaptations have remained elusive. Liver transplantation (LT) is a valuable yet scarce resource with the ability to transform the lives of patients with advanced liver disease. Despite improvements in anaesthetic management and surgical techniques, patients undergoing LT are at a substantial risk of perioperative cardiovascular complications. This is pertinent as transplant candidates in the contemporary era are often older and have a higher proportion of vascular comorbidities. In addition, non-alcoholic fatty liver disease is becoming a major aetiology of liver disease and this condition shares similar risk factors to many cardiovascular disease states. As such, optimizing risk stratification of patients prior to LT is a priority to ensure optimal patient and graft outcomes. Moreover, whether transplantation itself confers risk of accelerated atherosclerosis is unclear. This dissertation work explores three key areas. First, it aims to provide an extensive review of the perioperative and long-term cardiovascular mortality of patients undergoing LT in Australia and New Zealand. Second, we investigate the pathophysiological connections that constitute the heart-liver axis in patients with end-stage liver disease undergoing LT. This covers both the structural and electrophysiological alterations that characterize cirrhotic cardiomyopathy with a translational focus. Third, we aimed to evaluate predictors of cardiovascular events in patients undergoing LT, including a prospective study evaluating whether LT leads to accelerated changes in coronary atherosclerosis. Collectively, this thesis explores key epidemiologic data relating to cardiovascular mortality in the LT population, and highlights key cardiac structural, electrophysiological and coronary disease manifestations in patients with end-stage liver disease undergoing transplantation.
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ItemThe effect of gender-affirming hormone therapy on the health and well-being of transgender Australians( 2021)There is increasing demand for gender-affirming hormone therapy, used by transgender individuals to align physical characteristics with their gender identity. Although hormone therapy improves quality of life and psychological functioning, significant barriers to accessing appropriate healthcare persist. Hormone therapy is often started at a young age and continued lifelong, yet little is known about the long-term effects on metabolic and bone health, both highly regulated by sex hormones. Our aim was to understand the sociodemographic characteristics of transgender Australians, the level of training and confidence of Endocrinologists in transgender health, and the prescribing practices of experienced medical practitioners. We report findings from a series of surveys. Transgender adults (n=928) reported alarmingly high rates of self-harm (63%), attempted suicide (43%) and discrimination within healthcare settings (26%). Barriers included difficulties navigating the healthcare system and finding doctors to prescribe. Better training for doctors was a priority with only 4% of Endocrinologists and trainees (n=147) reporting any training in transgender health during medical school, 91% desired more training. Experienced prescribers (n=35) displayed uniformity in prescribing practices, despite a lack of local guidelines. We then investigated the effects of hormone therapy on cardiovascular risk and bone microstructure. Transgender individuals face higher metabolic risk due to sex hormone mediated changes in body composition and insulin resistance. Bone morphology may be compromised as estradiol is a key regulator of bone remodelling. Transgender adults on established hormone therapy, and control participants, underwent body composition scanning (dual energy X-ray absorptiometry) and quantification of bone microstructure (high-resolution peripheral quantitative CT). Trans men (n=43) had higher mean lean mass, +7.8kg (4.0, 11.5) p<0.001, similar total fat mass but higher android:gynoid fat ratio when compared to female controls (n=48). Insulin resistance was similar, indicating a protective effect of higher lean mass. Conversely, trans women (n=41) had lower mean lean mass, -6.9kg (-10.6, -3.1), p<0.001, higher fat mass, +9.8kg (3.9, 14.5), p=0.001, and lower android:gynoid fat ratio when compared to male controls (n=30). Although android fat correlated more strongly with insulin resistance, trans women had higher insulin resistance likely due to higher overall fat mass. Bone microarchitecture was not compromised in trans men (n=41), as aromatisation of administered testosterone to estradiol likely prevented bone loss. Trans men had higher distal tibial total volumetric bone density (vBMD), 0.71 SD (0.30, 1.12), p<0.01, preserved cortical morphology and trabecular bone volume fraction relative to female controls (n=71). Despite estradiol administration, trans women (n=40) were not protected from microarchitectural deterioration, indicating the dose was insufficient to offset reduced aromatisable testosterone. Trans women had -0.55 SD lower distal tibial total vBMD (-1.01, -0.08), p=0.02 due to higher cortical porosity, 0.63 SD (0.19, 1.07), p=0.01 and lower trabecular bone volume fraction relative to male controls (n=51). Our survey findings informed new Australian clinical practice guidelines and a new gender service. Our cross-sectional study not only provide new and important insights into sex hormone action but are also highly clinically significant, given proactive measures can be implemented to mitigate fat gain and bone loss, particularly in trans women.
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ItemThe epidemiology of Primary Biliary Cholangitis in Australia( 2021)1.1 INTRODUCTION PBC has received little attention in the medical literature. Unlike many other liver diseases, such as viral hepatitis, there have been few advances in the understanding of disease aetiology or in available treatments. In the last 20 years only one additional well-validated and efficacious therapy has been established for this disease for those who do not respond to UDCA. PBC remains a rare condition but the prevalence of this disease is increasing. Previous work from our centre also demonstrated an increase in the prevalence of PBC and increasing prevalence amongst migrant populations (Sood, Gow et al. 2004). However there have been no Australian studies since 2002. The disease prevalence appears to be increasing in North America, Europe and Asia but it is unknown whether this was also the case for Australia. Therefore the study outlined in Chapter 3 evaluated PBC prevalence in Victoria, Australia and compared this to two previous Victorian studies (Watson, Angus et al. 1995, Sood, Gow et al. 2004). There is a precedent in other immune mediated disease, most notably Multiple Sclerosis (Simpson, Wang et al. 2019), for a latitudinal gradient of prevalence however this has never been evaluated in primary biliary cirrhosis. Therefore, the study in Chapter 4 evaluated whether there was an association between PBC prevalence and latitude. It is now well established that PBC is associated with recurrent urinary tract infections (Parikh-Patel, Gold et al. 2001, Gershwin, Selmi et al. 2005, Corpechot, Chretien et al. 2010, Prince, Ducker et al. 2010) and smoking (Howel, Fischbacher et al. 2000, Gershwin, Selmi et al. 2005, Corpechot, Chretien et al. 2010, Prince, Ducker et al. 2010) however there is a clear gap in our understanding of aetiopathogenesis of the disease, with the already known genetic associations and established environmental risk factors only explaining part of the risk. Thus there is a need for further detailed case control studies to evaluate other potential associations. We designed a case-control study to examine multiple environmental factors including the relationship between sunlight, ultraviolet radiation and PBC (Chapter 5). There is also paucity in the literature on robust case control studies examining the relationship between alcohol and PBC and therefore we conducted a case control study to examine this relationship in more detail (Chapter 6). Further study of PBC epidemiology is beneficial as it determines the burden of disease in Australia and whether there are any modifiable risk factors for susceptible individuals. It will also have implications for future treatment pathways. 1.2 AIMS 1. To determine the 2013 prevalence of PBC in Victoria, Australia, and to determine the time trend by comparing it with previous studies undertaken in 1991 and 2002. 2. To evaluate whether there is a latitude gradient of this disease in Australia. 3. To assess whether reduced past sun exposure is associated with an increased risk of PBC development in a case control study. 4. To assess the relationship between alcohol intake, tobacco smoking and marijuana use with PBC in a case control study. 1.3 METHODS 1.3.1 2013 Victorian PBC prevalence study In 2014, we conducted a prevalence study in Victoria to determine the 2013 prevalence of the disease. Four methods were used to identify patients with PBC: (1) Physicians’ survey: a survey was sent to all registered gastroenterologists and hepatologists in Victoria, (2) Tertiary hospital search: a medical record search for cases of PBC recorded between 1 January 2003 and 1 January 2013, at Victoria’s seven major teaching hospitals (Austin Hospital, Eastern Health, Royal Melbourne Hospital, Alfred Hospital, Western Hospital, Monash Medical Centre and St Vincent’s Hospital), (3) Liver Transplant Database search: I undertook a search of the Victorian Liver Transplant Unit database, based at the Austin Hospital (Heidelberg, Victoria) and (4) Private Pathology AMA search: the three major private pathology companies in Victoria provided all positive AMA results (titre >1:40) and corresponding liver function tests for patients from 1 January 2003 to 1 January 2013. 1.3.2 Latitude study To examine the latitude gradient of PBC in Australia, we needed a method of case identification that was uniform across Australia. Even if the method provided an underestimate of the true prevalence, as long as there was no systematic bias by latitude, we would still obtain solid evidence of the existence or absence of a latitudinal gradient of the disease. We decided to pursue two options. A probable diagnosis of PBC is made with a positive AMA and corresponding cholestatic liver function tests. We obtained all positive AMA results (titre>1:40) and corresponding liver function tests for the states/territories of Queensland, New South Wales, the Australian Capital Territory, South Australia, Victoria, and Tasmania for a three-year period (2010-2013) from the three major pathology companies in Australia. The second method of PBC case identification used the ursodeoxycholic acid (UDCA) prescription data sourced from Medicare Australia by state from January 2010 to December 2013. Medicare Australia provided the number of PBS and RPBS prescriptions of UDCA prescribed in the three-year period in each state and territory of Australia from January 2010–January 2013 inclusive. 1.3.3 PBC case control study From 1 January 2015 to 31 October 2017, we conducted the PBC case control study of 200 PBC cases and 200 age and sex-matched controls. The environmental questionnaires included: place of birth, ethnicity, educational level, medical history including personal and family history of autoimmune diseases, history of infectious diseases including urinary tract infections, reproductive history, surgical history, history of tobacco smoking, marijuana use, past alcohol intake, occupational history, occupational exposures and exposure to chemicals and significant life events. For cases this also included age of diagnosis, method of diagnosis and symptoms at diagnosis (Appendix 1, 2). Sun exposure was assessed in a number of different ways. The first sun exposure measure utilised a personal residence and work calendar (Appendix 3). Subjects were sent this calendar prior to the interview and asked to fill in their place of residence and occupation for each year of their life. During the interview, subjects were asked how much time they spent in the sun for each of the years identified in the pre-filled questionnaire for summer and winter from age 6 until the time of interview. The second sun exposure measure utilised a verbal questionnaire. Subjects were asked about the amount of time they would normally have spent in the sun during weekends and holidays for winter and summer using validated questions (van der Mei, Blizzard et al. 2006). The face-to-face interview also involved a physical examination. Skin phenotype was assessed with a hand held Minolta 508 spectrophotometer at the upper inner arm and buttock, body sites that are not usually exposed to sunlight. Cutaneous melanin density was estimated from skin reflectance of light centred at 400nm and 420nm. The subjects had 35 millilitres of blood collected for biochemistry and 25(OH)D levels. We also measured their weight and height and examined subjects for stigmata of chronic liver disease (Appendix 4). 1.4 CONCLUSIONS This thesis has evaluated the epidemiology of PBC in Australia by determining an accurate prevalence of disease and identifying, for the first time, that there is a latitude gradient of disease in Australia. Through a case control study we have confirmed the known association of PBC and tobacco smoking. We have also identified somewhat controversially that past alcohol intake is associated with a lower risk of developing PBC. We have performed the first case-control study evaluating the relationship with past exposure to sunlight and ultraviolet radiation with PBC and have identified that reduced sunlight and UV exposure are potential risk factors for the development of disease, which, if confirmed, could result in balanced sun exposure recommendations specifically targeted at those who are at risk of PBC.
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ItemNovel approaches to risk stratification in common cardiovascular diseases using circulating and imaging biomarkers( 2021)Cardiovascular disease (CVD) is a leading cause of morbidity and mortality. The number of individuals at risk of CVD complications continues to rise, making CVD preventative strategies an ongoing public health priority. Current risk-stratification approaches have limited predictive value, which poses a significant challenge in delivering preventative therapies. Therefore, finding new biomarkers for CVD is of interest and may improve the identification of individuals who would benefit most from preventative therapies. The main aim of this thesis was to identify novel approaches to risk stratification in common CVD states using circulating and imaging biomarkers. This thesis consists of four studies that evaluated: 1) The prognostic role of circulating angiotensin converting enzyme 2 (ACE2) in coronary artery disease (Chapter 3); 2) The role of circulating and myocardial ACE2 in aortic stenosis (Chapter 4); 3) The role of abnormal myocardial tissue characterisation using native T1 time, a cardiac magnetic resonance technique in aortic stenosis (Chapter 5); and 4) The role of opportunistic screening using cardiac computed tomography (CT) to identify markers of vascular disease such as coronary artery calcium and thoracic aortic dilation in atrial fibrillation (Chapter 6). The first study (Chapter 3) was a prospective evaluation of circulating ACE2 levels in patients with obstructive coronary artery disease. ACE2 is an integral membrane protein that degrades angiotensin II and has an emerging role as a circulating biomarker of CVD. Over a median follow up of 10.5 years, circulating ACE2 activity independently predicted the occurrence of major adverse cardiovascular events (MACE) [hazard ratio (HR) 2.4, 95% confidence interval (CI) 1.24–4.72]. The second study (Chapter 4) investigated the relationship between circulating ACE2 activity levels and all-cause mortality in patients with aortic stenosis. Additionally, the relationship between circulating ACE2 activity, myocardial ACE2 gene expression, and myocardial fibrosis were examined. Higher circulating ACE2 levels were associated with increased myocardial structural abnormalities such as increased LV mass index and increased LV volumes. Over a median follow-up of 5 years, elevated circulating ACE2 activity was an independent predictor of all-cause mortality with incremental prognostic value after adjustment for relevant clinical, imaging, and biochemical parameters (HR: 2.28; 95% CI: 1.03 to 5.06). In a subset of patients with myocardial tissue collection, increased circulating ACE2 was associated with reduced myocardial ACE2 gene expression and severe myocardial fibrosis. The third study (Chapter 5) investigated whether diffuse myocardial fibrosis characterised by greater native T1 times on cardiac magnetic resonance provides prognostic utility to predict MACE (all-cause mortality or heart failure hospitalisation) in patients severe AS being evaluated for transcatheter aortic valve replacement. Native T1 times were higher than previously reported values in healthy controls. Patients with higher T1 times were more likely to have evidence of myocardial decompensation demonstrated by higher NT-proBNP levels and lower left ventricular ejection fraction. Over a median follow-up of 3.1 years, increased native T1 time (HR:1.68; 95% CI:1.08 - 2.62) and age > 75 years (HR:1.82;1.01–3.28) were independent predictors of MACE. The fourth study (Chapter 6) investigated the prevalence of incidental vascular diseases, including thoracic aortic aneurysmal disease and coronary atherosclerosis, both important causes of cardiovascular mortality, in patients with atrial fibrillation. In a cross-sectional study of 1,000 consecutive patients with atrial fibrillation, one in five were found to have newly identified thoracic aortic aneurysmal disease on multidetector chest CT. A small proportion (1%) had significantly aneurysmal dimensions that approached surgical thresholds. Although two-thirds of the cohort had coronary calcification, 38% were not taking lipid-lowering therapy. The findings therefore represent an opportunity to substantially optimise preventative measures in AF. Overall, the findings of the thesis suggest that the circulating and imaging biomarkers evaluated in the above studies, provide incremental diagnostic and/or prognostic information in patients with CVD. The findings need confirmation in large independent cohorts before these biomarkers can be incorporated into risk stratification algorithms.
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ItemThe effect of sodium on sympathetic nervous system activity and endothelial function in people with type 2 diabetes( 2020)Lowering dietary sodium intake is recommended by public health bodies to lower blood pressure with the ultimate aim of reducing cardiovascular-related disease. However, lower sodium intake has been demonstrated in observational studies to be associated with adverse health outcomes such as higher cardiovascular-related morbidity and mortality in people with type 2 diabetes. They may be due to pleiotropic effects of sodium lowering, such as activation of the renin-angiotensin-aldosterone system (RAAS) and increases in circulating adrenaline and noradrenaline. Dedicated intervention trials are lacking but greatly needed to investigate the complex role of sodium on cardiovascular outcomes further. In an effort to underpin the mechanistic links behind the associations between low sodium intake and poorer cardiovascular outcomes in people with type 2 diabetes, the studies presented in this thesis aimed to examine the effect of sodium on cardiovascular health by measuring the primary endpoints of sympathetic nervous system activity, as assessed by microneurography, and endothelial function, as assessed by endoPAT and endothelial microparticle measurements, and the secondary endpoints of cardiac baroreflex, serum aldosterone, as markers of RAAS activity, and simultaneous measures of 24h blood pressure and heart rate variability. We demonstrated, that compared to other groups along the glucose continuum, individuals with treated type 2 diabetes who had low sodium intake presented with worse endothelial and baroreflex function. This occurred even though these individuals were appropriately managed for their cardio-metabolic risk factors and importantly, adhered to recommended low sodium intake guidelines. This study provided the rationale to conduct an interventional study where, for the first time, we assessed the effect of salt supplementation on cardiovascular endpoints of sympathetic activity and endothelial function as assessed by endoPAT, in people with type 2 diabetes. Salt supplementation was associated with a small increase in sympathetic activity. However, this did not reach levels associated with pathological disease states. Importantly, there were no detrimental effects on endothelial function or alterations in blood pressure. Interestingly improvements in baroreflex function and RAAS activity were seen. When participants were categorized based on salt-sensitivity, salt-resistant individuals demonstrated a trend towards improved endothelial function after salt supplementation. To explore the endothelial response further, we examined the association between habitual sodium intake, RAAS blockade, and endothelial function as assessed by circulating microparticles. Despite expecting higher endothelial microparticles being associated with lower sodium intake, we did not demonstrate any significant association between sodium intake and endothelial microparticles. However, we observed a trend towards higher erythrocyte-derived microparticle levels being associated with lower sodium excretion and higher platelet-derived microparticles being associated with the lowest tertile of 24hUNa excretion. Additionally, RAAS blockade was not associated with lower microparticles counts in the setting of a low sodium intake, questioning whether the therapeutic benefits of RAAS blockade may be attenuated during lower sodium intake. Despite public health bodies advocating for lowering dietary sodium, we demonstrated that these guidelines are simply not being met and sodium intake is unlikely to change over time. Furthermore, we compared the two most common methodologies used to estimate sodium intake in cardiovascular outcome trials which have largely formulated the basis of dietary sodium guidelines. We demonstrated poor agreement between 24h dietary recall and 24h urine sodium excretions, likely due to underestimation and underreporting of sodium intake via 24h dietary recall. Taken together, these findings begin to provide mechanistic insight that sodium lowering in people with type 2 diabetes may not provide the benefit on the sympathetic and endothelial system as intended. Therefore, the necessity for stringent sodium lowering is questioned in this population. Our studies additionally demonstrate the need for future studies to use sound methodological approaches to determine the ideal yet feasible dietary sodium intake targets in people with type 2 diabetes.
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ItemThe Association Between Mitral Valve Prolapse With Ventricular Arrhythmias and Sudden Cardiac Death( 2020)The mitral valve is one of four heart valves, and is situated between the left atrium and left ventricle. Its role is to facilitate the unidirectional flow of blood through the left atrium and ventricle by opening in diastole and closing in systole. Mitral valve prolapse (MVP) involves the atrial displacement of the mitral valve during ventricular systole. While MVP has been linked to the development of sudden cardiac death (SCD) through the development of malignant ventricular arrhythmias (VAs), this association remains controversial. This thesis examines the relationship between MVP, VAs and SCD. Chapter 1 reviews the published literature surrounding MVP, VAs and SCD. A historical context and contemporary link between MVP and SCD are discussed. Various histopathological, cardiac imaging and electrophysiological findings in MVP and VAs or SCD are explored. The current pathophysiological understanding of SCD in MVP is highlighted, and provides a premise for subsequent chapters. Chapter 2 systematically reviews all cases of MVP and SCD reported in the literature. The cases in the literature describe a predominantly young, female population with frequent premature ventricular complexes (PVCs) and prolapse involving both mitral valve leaflets. Cardiac arrest usually occurs as a result of ventricular fibrillation. Leaflet redundancy (defined as thickness greater than or equal to 5mm) is the only independent predictor of SCD. Chapter 3 describes histopathological findings and cardiac arrest rhythm in individuals with isolated MVP (iMVP, whereby other potential causes of death are excluded) and SCD. Individuals with iMVP-SCD have increased cardiac mass, mitral annulus size and left ventricular fibrosis compared to a control group matched for age, sex, height and weight. In those with iMVP and witnessed cardiac arrest, ventricular fibrillation is the predominant cardiac arrest rhythm. These findings suggest that histopathological changes in MVP may provide the substrate necessary for the development of VAs leading to SCD. Chapter 4 comprehensively and systematically quantifies left and right ventricular fibrosis in individuals with iMVP-SCD compared to a matched control group. Individuals with iMVP-SCD have more left ventricular and interventricular septum fibrosis but similar degree of right ventricular fibrosis compared to the control group. In those with iMVP-SCD, there is more fibrosis in the lateral and posterior walls of the left ventricle with an endocardial-epicardial gradient of fibrosis, which is similar to other conditions that cause cardiac remodelling. These findings indicate that non-uniform left ventricular remodelling with both localised and generalised fibrotic changes are important in the pathogenesis of SCD in MVP. Chapter 5 compares the incidence of VAs detected with continuous cardiac rhythm monitoring in patients with MVP and controls, and examines whether certain factors predicted for the development of VAs within the MVP group. Over a 24-month follow-up period, those with MVP had a significantly higher overall incidence of VAs compared to control groups. Within the MVP group, the presence of late gadolinium enhancement on cardiac magnetic resonance imaging was predictive for the development of VAs. Chapter 6 evaluates the role of mitral regurgitation and mitral valve surgery with regards to VAs in patients with redundant leaflet MVP. In patients with redundant leaflet MVP, severity of mitral regurgitation does not affect PVC burden while mitral valve surgery does not reduce PVC burden in unselected patients with MVP. Based on the significant change in PVC burden in two patients, the role of mitral valve surgery in selected patients with MVP warrants further investigation.
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ItemThe effects of lung volume recruitment therapy on respiratory function and quality of life in people with neuromuscular disease( 2020)Respiratory muscle weakness results in substantial discomfort, disability and ultimately death in many neuromuscular diseases (NMDs). Respiratory compromise manifests as some or all of, shallow breathing, poor cough and associated difficulty clearing mucus, respiratory tract infections, hypoventilation, sleep-disordered breathing and chronic ventilatory failure. As survival outcomes improve for many NMDs, there is a shift towards more proactive and preventative chronic disease multi-disciplinary care models that manage symptoms, improve morbidity and reduce mortality. Unfortunately, clinical care guidelines for chronic NMD care are based largely on clinical rationale and consensus opinion rather than level A evidence. These guidelines typically recommend therapies to enhance lung inflation and cough effectiveness, however there is minimal evidence that performing techniques regularly is beneficial. Lung volume recruitment (LVR) is one such therapy. Simple, inexpensive and widely-accessible, it delivers air via a manual resuscitation bag to augment lung inflation above a person’s own deepest breath. Given the absence of prospective controlled research, this thesis aimed to investigate the effect of regular LVR in people with NMD. Firstly, a cross-sectional cohort study of 80 community-dwelling adults with NMD and respiratory system impairment identified that participants with slowly-progressive forms of NMD have smaller lung volumes and respiratory system compliance (Crs) than participants with rapidly-progressive motor neurone disease, despite having a similar degree of respiratory muscle weakness. Stiffness was associated with smaller lung volume in long-standing NMD, supporting the hypothesis that maintaining lung volume and Crs may ameliorate respiratory decline. The second component of this thesis confirmed the feasibility of LVR; 95% of participants naïve to the therapy could successfully augment their lung insufflation capacity (LIC, the maximum inflation capacity obtained by assisting inflation). Moreover, LIC and Crs increased following a single-session of LVR therapy. These immediate effects were only evident when naïve; when assessed three-months later there was no change in respiratory function following a single-session of LVR. The third and primary component of this work, a randomised controlled trial of twice-daily LVR or an active control treatment for three-months, found a statistically significant difference in LIC between groups favouring LVR. No demonstrable change in lung volumes, respiratory muscle strength, symptoms or quality of life was found, suggesting a learning effect or acclimatisation to higher inflation pressures may be responsible for the increase. However, an improvement in Crs predominantly in the LVR group means a beneficial effect on underlying respiratory mechanics cannot be excluded, especially if conducted for a longer duration. Notwithstanding the need for further longitudinal studies, the observed improvement in the primary outcome of LIC in the absence of apparent harm or burden, provides robust preliminary data supporting clinical recommendations and practice that regular LVR be performed by people living with NMD. The clinical significance of a higher LIC is still to be fully realised, but this thesis has demonstrated an effect that is compatible with the clinical and biologically-plausible rationale for this therapy.
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ItemPredictors of Relapse in Polymyalgia Rheumatica Patients Treated with Low-Dose Glucocorticoid Therapy( 2020)Polymyalgia rheumatica (PMR) is a chronic inflammatory condition characterised by subacute onset shoulder and pelvic girdle pain, and early morning stiffness. Oral glucocorticoids represent the treatment mainstay and whilst cessation of therapy is the goal, a subset of patients with relapsing disease remains poorly delineated. This thesis aimed to characterise the demographic, clinical, laboratory and imaging phenotype of patients that relapse by undertaking a prospective longitudinal cohort study of newly diagnosed, steroid naive PMR cases (2012 EULAR/ACR classification criteria) treated with a weaning schedule of prednisolone (BSR guideline). Disease relapse, as defined by the PMR activity score (PMR-AS), represented the primary outcome measure and was observed in 25/32 participants (78.1%) during the 46-week follow-up period. Older age at diagnosis (HR 1.07) and female sex (HR 2.38) were subsequently associated with an increased risk of relapse, whilst a volar pattern of 18F-FDG uptake on whole body PET/CT conferred a distinct prognostic advantage (HR 0.25). Half of the study participants also met criteria for the secondary endpoint of glucocorticoid-resistant disease. Baseline predictors for this outcome again included older age and female sex, along with high BMI and high neutrophil to lymphocyte ratio (NLR). Results from this work additionally informed a proof-of-concept PET/MRI fusion study identifying hamstring peritendonitis as the anatomic correlate of abnormalities observed adjacent to the ischial tuberosities. A nested case-control subsequently achieved a sensitivity of 90.9% and specificity of 92.4% for diagnosing PMR on whole body PET/CT based upon a novel scoring algorithm that combined this finding with other key sites of extra-capsular pathology. Finally, data was utilised for preliminary validation of candidate instruments being considered for inclusion in a PMR core outcome measurement set to be endorsed by the international body, OMERACT. Overall, the findings presented in this thesis confirm the hypothesis that discrete phenotypic differences exist among PMR patients with relapsing disease and make a substantive novel contribution to the literature concerning the pathology, diagnosis, monitoring and management of this rheumatic disease. The low incidence of sustained clinical remission observed in this study following a standardised wean of glucocorticoid therapy should however serve as a timely reminder of the ongoing need for an alternate treatment paradigm in PMR.