Medicine (St Vincent's) - Theses
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ItemThe role of the coronary vasculature and myocardium in the pathogenesis of diabetic cardiomyopathy( 2012)The prevalence of diabetes is increasing worldwide. This poses a significant threat to human health, as diabetes is associated with an increased risk of mortality due to cardiovascular disease. In particular, diabetic patients develop diabetic cardiomyopathy (DCM), characterised by impaired cardiac muscle contraction and relaxation, leading to left ventricle (LV) muscle stiffness and congestive heart failure. Previous studies suggest that changes in the coronary vasculature and cardiac subcellular function may account for the progression to DCM, however as yet this has not been assessed in vivo. Synchrotron radiation (SR) now makes possible novel imaging and diffraction techniques, to investigate the role these mechanisms play in the early development of DCM, where clinical intervention is most efficacious. To assess coronary function in vivo we validated the use of SR imaging to detect and quantify regional differences in resistance microvessel calibre. In type 1 diabetic rodents we found that although endothelium-dependent and –independent vasodilatory responses in individual coronary vessels are preserved, following inhibition of NO and PGI2 production, there is evidence of localised focal and segmental constrictions. This demonstrates, for the first time, localised coronary microvascular endothelial dysfunction in early-stage type 1 diabets (T1D). Contributing to this diabetic coronary impairment is the RhoA/Rho-kinase (ROCK) pathway, which had previously been shown to play a role in endothelial dysfunction and coronary vasospasm. Our data further support a role for ROCK in early diabetic coronary dysfunction, as following nitric oxide synthase/cyclooxygenase blockade, ROCK inhibition greatly reduced regional segmental constrictions and completely alleviated persistent focal stenoses in diabetic animals. Together, these findings provide strong evidence that early vascular dysfunction may contribute to the development of DCM. In addition, although characterised by global cardiac impairment, the role subcellular changes in the sarcomere play in DCM progression is not known. SR, as a source for small-angle X-ray diffraction, allows the assessment of cardiomyocyte cross-bridge dynamics (CB) and myosin interfilament lattice spacing in situ and in real time. Using SR, our data shows that in early T1D, CB dynamics are abnormal in the beating hearts and this is directly related to impaired LV function. The change in CB dynamics is caused by myosin head displacement from actin filaments, but notably is not related to estimated sarcomere length or myofilament order. SR X-ray diffraction thus provides a robust method to assess cardiac CB dynamics in situ and for the first time we provide evidence that impairment in the regulation of myosin head extension in T1D hearts contributes to DCM. Currently 85-90% of diabetics have T2D and it is therefore critical that these coronary microvascular and cardiac subcellular impairments in T1D are explored in T2D. As such, rodent models which account for the environmental factors important in the human development of DCM are required. We conducted a comprehensive characterisation of cardiac function and structure in diet-induced rodent models of obesity, insulin resistance and T2D, and uncovered mild systolic dysfunction in fructose fed and mild diastolic dysfunction in high fat fed rodents. Furthermore, we demonstrated mild contractile dysfunction in high fat fed low dose streptozotocin rodents. The characterisation of only mild cardiac dysfunction, in spite of the lengthy time course used, suggests further refinement is required to achieve more robust DCM models. In summary, through the validation of novel SR imaging and diffraction techniques our data has confirmed a role for coronary microvascular dysfunction, via the ROCK pathway and cardiac subcellular impairment, via reduced myosin head extension, in the development of DCM. In addition, further studies investigating rodent models of T2D and DCM are required. These findings provide a strong basis for the future development of novel therapies aimed at preventing and/or reversing the decline in cardiac function associated with diabetes.
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ItemAetiology of structural and functional remodelling of the right ventricle in endurance athletes( 2010)Endurance exercise training results in changes in cardiac structure and function which have been more thoroughly characterised for the left ventricle (LV) than for the right ventricle (RV). Recent evidence suggests that intense prolonged exercise may result in myocardial dysfunction which predominantly affects the RV, and that chronic RV remodelling may represent a substrate for ventricular arrhythmias in athletes. The reasons underlying the predilection towards RV dysfunction with intense prolonged exercise and the variation between individuals in its occurrence are not known, but may include haemodynamic, neurohormonal and genetic factors. This work seeks to describe the acute and chronic effects of strenuous exercise on the RV. Changes in RV function are described relative to LV function in both endurance athletes and non-athletes. Whereas most previous investigations of cardiac function in athletes have been performed at rest, a key element of this thesis is the exploration of changes in haemodynamics and myocardial function during exercise. To enable thorough assessment of RV function, established and novel echocardiographic measures are validated against cardiac magnetic resonance imaging values. A comprehensive description of resting cardiac morphology is used to demonstrate that, relative to non-athletes, cardiac remodelling is greater in endurance athletes and that the remodelling is greater for the RV than the LV. As a potential explanation for this ventricular asymmetry, systolic wall stress was quantified during acute exercise and determined to increase to a greater extent in the RV than the LV. As a potential modulator of the load on the RV during exercise, exercise-induced pulmonary vascular changes are described by studying the pulmonary transit of agitated contrast (PTAC). Relationships between the extent of PTAC and both RV afterload and structure were identified and measures which may predict favourable RV afterload are proposed. The effect of intense prolonged exercise of differing durations was assessed and it was determined that myocardial dysfunction of the RV, but not the LV, is common and increases with exercise duration. Parameters determined during acute exercise testing were not predictive of RV dysfunction following intense prolonged exercise. In subsequent chapters, potential neurohormonal, inflammatory and genetic explanations for acute and chronic RV dysfunction in endurance athletes are explored, but do not appear to account for RV abnormalities in athletes. This thesis serves to expand the current understanding of RV function in athletes by demonstrating that RV remodelling is profound and is influenced by the differential acute haemodynamic influences of exercise on the right ventricle. RV function should be considered in future studies in which the clinical consequences of athletic cardiac remodelling are assessed.