Medicine (St Vincent's) - Theses
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ItemIntegration of advanced echocardiographic metrics and biomarkers to the fields of heart failure and exercise physiology in the era of precision medicine( 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.
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ItemFibrosis in experimental diabetic nephropathy and cardiomyopathy: effects of FT011, a novel anti-fibrotic intervention( 2011)It is estimated that by 2025, 366 million people worldwide will be diagnosed with diabetes mellitus (DM); this brings with it the potential for an increase in the prevalence of diabetic nephropathy (DN) and cardiomyopathy (DCM). Despite current management for diabetes, DN is the leading cause of end stage of kidney disease (ESKD) for renal replacement therapy, and DCM is associated with a higher incidence of chronic heart failure (CHF). Pathological fibrosis is a hallmark of progressive renal and cardiac disease leading to ESKD and CHF. Growth factors such as transforming growth factor β (TGF-β) and platelet-derived growth factor (PDGF) have been consistently implicated in the fibrogenesis in DN and DCM. Therefore, strategies inhibiting the bioactivities of these cytokines are becoming valuable anti-fibrotic therapeutic targets. Tranilast is one of series compounds that have been shown to inhibit actions of TGF-β and PDGF. To optimise the anti-fibrotic effects of tranilast, FT011 (Fibrotech Therapeutics, Pty. Ltd, Melbourne, Australia) is a newly synthesized compound based on cinnamoyl core structure of tranilast. The hypothesis of the thesis is that targeted treatment for fibrosis with FT011 will attenuate functional and structural manifestations of injury in experimental DN and DCM. The aims of this thesis were to firstly evaluate the inhibitory effects of FT011 on collagen synthesis and cell proliferation in vitro and in vivo models, and then to explore therapeutic effects of FT011 in experimental DN and DCM. In cultured rat mesangial cells, FT011 inhibited TGF-β1 and PDGFBB induced collagen production and cell proliferation in a dose dependent manner with no evidence of cell toxicity. Consistent with these actions, treatment of anti-Thy1 nephritis with FT011 attenuated matrix accumulation, mesangial phenotypic changes, mesangial cell proliferation and glomerular macrophage infiltration. These findings suggest a promising profile of FT011 for its potential use as an anti-inflammatory and anti–fibrotic drug. Progressive DN is characterised by glomerulosclerosis and tubulointerstitial fibrosis leading to capillary rarefaction with consequent loss of renal parenchyma and function. Both early and late intervention with FT011 in diabetic Ren-2 rats, a clinically predictive experimental model of DN, prevented development of albuminuria, tubulointerstitial fibrosis, and glomerulosclerosis. In addition, treatment of diabetic Ren-2 rats with FT011 was associated with a reduction in loss of glomerular capillary endothelial cells, interstitial macrophage accumulation and tubular cell apoptosis. These findings prove the hypothesis that targeted treatment for fibrosis with FT011 would attenuate renal functional and structural injury in experimental DN. Pathologically, DCM is associated with microvascular disease and characterised by myocyte hypertrophy, apoptosis and accumulation of interstitial matrix. These structural changes ultimately lead to heart dysfunction. Treatment of diabetic Ren-2 rats with FT011 attenuated systolic and diastolic dysfunction associated with reduction in interstitial fibrosis and myocyte hypertrophy. These findings prove the hypothesis that anti-fibrotic and anti-hypertrophic therapy with FT011 would attenuate heart dysfunction in DCM. The anti-fibrotic effects of FT011 observed in diabetic kidney and heart are independent of changes in high blood pressure and glucose, and the anti-fibrotic therapeutic efficacy of FT011 is greater than previous studies with tranilast. In addition, treatment with FT011 reduced ERK1/2 MAP kinase phosphorylation in both the diabetic kidney and heart. These findings suggest that anti-fibrotic mechanism actions of FT011 are different from blood pressure and glucose lowering agents and may be attributable to events that are more down stream signalling pathways of TGF-β, although the precise mode of action for FT011 was not determined in the present thesis. In conclusion, the findings of the present thesis advocate the use of strategies that target treatment for fibrosis by inhibiting bioactivities of pro-fibrotic cytokines delays the progression of DN and DCM. These findings yield important preclinical information in terms of the potential utility of FT011 as a novel anti-fibrotic therapy in the treatment of DN and DCM.