Medicine (St Vincent's) - Theses
Permanent URI for this collection
Now showing 1 - 3 of 3
ItemIntegration of advanced echocardiographic metrics and biomarkers to the fields of heart failure and exercise physiology in the era of precision medicineMoneghetti, Kegan James ( 2018)Exercise testing is widely used for risk stratification of ischaemic heart disease, however, its application in other cardiovascular conditions, specifically heart failure and other disease states is less defined. Heart failure is a leading cause of mortality and morbidity. Despite advances in medical therapy, its prevalence is expected to increase. Recent developments in cardiac echocardiography, exercise testing and reducing costs of biomarker assays provides the opportunity to improve identification and prognostication of the heart failure syndrome. These principles may also prove useful in the discrimination of other disease states, in which a diagnostic biomarker is lacking. The principle aim of this thesis was to identify novel echocardiographic and non-invasive cardiopulmonary parameters during exercise that provide incremental prognostic value to established risk markers in heart failure. An exploratory sub aim was to investigate the ability of a personalised exercise test to discriminated disease states outside the cardiovascular system. Cohorts of heart failure patients undergoing assessment with echocardiography and cardiopulmonary exercise testing were selected to assess the incremental value of novel parameters. Recently, deformation imaging, also known as strain and quantitative measures of the right heart have shown prognostic value in patients with heart failure. These measures have rarely been analysed with cardiopulmonary exercise testing, therefore, their prognostic value in outcome models and contemporary risk scores were assessed. Dynamic changes in selected parameters were evaluated with regard to risk stratification potential. Finally, as biomarker assays are becoming increasingly used to identify the heart failure syndrome, their contribution to discrimination of disease and risk modeling when performed in conjunction with an exercise test was evaluated. In summary the main findings of this thesis were: 1. Echocardiographic contractile reserve and cardiopulmonary exercise testing parameters provide complementary information, therefore, in combination provide an opportunity to improve prognostication in heart failure. 2. Right heart metrics specifically, right atrial volume and exercise performance add value to previously validated heart failure risk scores in dilated cardiomyopathy. 3. The combination of exercise performance, left ventricular strain and left atrial volume presents a simple model for predicting heart failure outcomes in hypertrophic cardiomyopathy. 4. Percent predicted values of maximal oxygen consumption derived from the Fitness Registry and the Importance of Exercise National Database (FRIEND) registry equation appear to accurately predict heart failure outcomes. 5. Cytokine profiling post exercise appears to have greater discriminatory power than at rest when used to identify patients with myalgic encephalomyelitis / chronic fatigue syndrome; Echocardiographic parameters, have limited value. 6. The integration of cardiac biomarkers, cytokine profiling, exercise performance and cardiac imaging in a personalised exercise test is achievable and has the potential to improve risk profiling. In conclusion, this thesis demonstrated the opportunity to further refine risk stratification in heart failure using novel images techniques, specifically deformation imaging, right heart metrics and exercise performance. The use of serum samples post a bout of exercise may provide an opportunity to further refine diagnostics in the field. Future studies should address biological variability of serum biomarkers and investigate their value when integrated with established markers of risk.
ItemContractile dysfunction of the heart in early diabetesWaddingham, Mark Thomas ( 2016)The prevalence of heart failure, especially heart failure with preserved ejection (HFpEF), is increasing annually in part due to an ageing population and the dramatically increased incidence of obesity, insulin resistance, prediabetes and diabetes worldwide. It is well established that patients with type-1 diabetes (T1DM) and type-2 diabetes (T2DM) are at a significantly increased risk of developing HFpEF. HFpEF is a progressive condition and its earliest manifestations are subtly impaired myocardial function that is termed diabetic cardiomyopathy (DCM). At present, there is only a limited understanding of the underlying pathophysiological mechanisms that drive the development of DCM and eventual HFpEF in early T1DM and T2DM. Therefore, the aim of this thesis was to further explore mechanisms that could drive the development of DCM and HFpEF using rat models of early T1DM and T2DM. Using synchrotron radiation as a source for small angle x-ray scattering (SAXS) in the in situ beating rat heart, we are able to measure actin-myosin cross-bridge (CB) dynamics in the entire cardiac cycle, in real time. In the first part of this thesis, we were able to demonstrate that chronic inhibition of the RhoA/Rho-kinase (ROCK) pathway with fasudil improved regionally impaired diastolic myosin head extension and depressed systolic mass transfer in the myocardium of rats with early T1DM. Further, we were also able to demonstrate that global left ventricular (LV) systolic performance was significantly improved in diabetic rats treated with fasudil. These results suggest that the activation of the ROCK pathway is involved in the development of early DCM in the context of T1DM. The Goto-Kakizaki (GK) rat is a non-obese model of spontaneous T2DM, which makes it a useful model to examine the effects of early T2DM on the myocardium without the added complication of obesity. Utilising the synchrotron radiation SAXS technique in the in situ beating heart preparation, we are able to demonstrate that young GK rats (10-12 weeks old) with early T2DM (prediabetes) exhibit impaired basal diastolic myosin head extension and reduced systolic myosin mass transfer in the deeper myocardial layer, the subendocardium. Interestingly, basal global cardiac function and β-adrenergic mediated positive inotropy was preserved in young GK rats. We speculate that a combination of cardiomyocyte hypertrophy and enhanced epicardial fibre function are the most likely mechanisms for the preserved global LV function in young GK rats. Diabetes is rarely seen in isolation in patients and commonly coexists with hypertension. The interaction of diabetes and hypertension is known to exacerbate myocardial dysfunction and accelerate the development of HFpEF, but the precise mechanisms remain elusive. The GK rat is a model of salt-sensitive hypertension induced by exposure to a high-salt diet (6% NaCl) for eight weeks. Thus, we examined if the interaction of prediabetes and salt-sensitive hypertension exacerbated myocardial dysfunction and accelerated the development of HFpEF in young GK rats. In GK rats exposed to a HS diet, we observed subtle declines in basal global diastolic and systolic LV function. Limited contractile reserve is a key feature of clinical HFpEF. Consistent with this, we were able to show that regional contractile reserve was limited at the fibre-level in the subepicardial and subendocardial fibre layers of the myocardium in GK rats maintained on a HS diet. These results suggest that limited contractile reserve at the fibre-level may be an early manifestation of HFpEF. In summary, this thesis has demonstrated that the ROCK pathway is involved in the evolution of DCM in T1DM, possibly by modulating actin-myosin interactions in the cardiac cycle. Our results also indicate that impaired CB dynamics is a feature of early T2DM DCM, although global cardiac function is preserved. Importantly, we have demonstrated that limited contractile reserve at the fibre-level may be an early manifestation of HFpEF in the presence of early T2DM and hypertension. Although further work is required to identify the specific molecular mechanisms that drive the impaired actin-myosin CB dynamics in early T1DM and T2DM, this thesis provides novel information of the pathophysiological features of contractile dysfunction of the heart in early diabetes.
ItemNovel synthetic flavonoids in acute and chronic heart and kidney diseasesKhong, Fay Lin ( 2012)Cardiovascular disease remains one of the leading causes of death worldwide despite the dramatic reduction in mortality rates over the past two decades due to significant advancement in medical and public health interventions. Diabetes exacerbates the complex interaction of cardiovascular risk factors, resulting in the greater incidence of heart failure among individuals with diabetes when compared to those without diabetes. The relative risk of cardiovascular mortality is further increased when individuals with diabetes are diagnosed with the comorbidity of established chronic kidney disease. Therefore, there is a continuous need for the development of novel therapeutic strategies to prevent the progression of cardiac and renal dysfunction in the presence or absence of diabetes, since the protective effects from the routine use of current pharmacotherapy for the management of elevated blood glucose, high blood pressure and abnormal blood lipid profiles remain limited and controversial. The focus of this thesis is to further elucidate the pathophysiological roles of oxidative stress and inflammation in the disease progression and to explore the therapeutic potential of novel synthetic flavonoids, DiOHF and NP202, in the prevention of acute and chronic heart and kidney diseases. Cardiovascular disease remains one of the leading causes of death worldwide despite the dramatic reduction in mortality rates over the past two decades due to significant advancement in medical and public health interventions. Diabetes exacerbates the complex interaction of cardiovascular risk factors, resulting in the greater incidence of heart failure among individuals with diabetes when compared to those without diabetes. The relative risk of cardiovascular mortality is further increased when individuals with diabetes are diagnosed with the comorbidity of established chronic kidney disease. Therefore, there is a continuous need for the development of novel therapeutic strategies to prevent the progression of cardiac and renal dysfunction in the presence or absence of diabetes, since the protective effects from the routine use of current pharmacotherapy for the management of elevated blood glucose, high blood pressure and abnormal blood lipid profiles remain limited and controversial. The focus of this thesis is to further elucidate the pathophysiological roles of oxidative stress and inflammation in the disease progression and to explore the therapeutic potential of novel synthetic flavonoids, DiOHF and NP202, in the prevention of acute and chronic heart and kidney diseases. The manifestation of acute myocardial infarction remains a major contributor to the subsequent development of heart failure despite the successful implementation of coronary reperfusion strategies. There has been substantial evidence showing that the dynamic progression of LV contractile dysfunction persisted up to several weeks following the restoration of coronary blood flow. The oral administration of NP202 during the reperfusion period in an experimental model of AMI resulted in the sustained improvement of LV contractile function in association with the reduction in the accumulation of inflammatory cells in the infarct zone of the heart even after seven days following the induction of AMI. This thesis has provided a strong basis for further therapeutic advancement of synthetic flavonoids as novel pharmacological agents to prevent the progression of heart and kidney diseases in the absence and presence of diabetes. There are clear indications that the modulation of oxidative stress and inflammation in the presence of synthetic flavonoids could be responsible for the prevention of the disease progression. The comprehensive understanding of the pharmacokinetics and oral bioavailability of the synthetic flavonoids is necessary for further preclinical evaluation of these promising therapeutic interventions. The enhancement of the biological actions of the synthetic flavonoids in the oral formulation would thus enable the translation of the basic research for potential clinical utility.