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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ItemRheumatoid arthritis, cardiovascular disease and inflammation.... and the effects of rheumatoid arthritis drug therapies on this musketeer trio( 2010)Rheumatoid arthritis (RA) is associated with a significantly higher rate of cardiovascular (CV) disease and mortality (1). The higher CV risk appears to be independent of traditional CV risk factors (2). Atherosclerosis is now recognised as an inflammatory disease, and the relationship between RA and CV disease may partly be explained by chronic systemic inflammation (3). Inflammation plays a role at all stages of the atherosclerotic process from the earliest stages of endothelial dysfunction to plaque development and eventually to plaque complications such as rupture and thrombosis which lead to clinical events such as heart attack and stroke (4). Medications commonly taken by RA patients may exacerbate or improve CV risk. Methotrexate improves RA disease activity, inflammation and CV mortality in RA (5). Non-steroidal anti-inflammatory medications (NSAIDs), cyclo-oxygenase inhibitors (COX-2 inhibitors) and TNFα-inhibitors are commonly used in RA with varying degrees of inflammation suppression. Their effect on CV risk in RA might therefore assist in our understanding of the complex relationship which we hypothesise exists between RA, CV disease and inflammation. The aim of this thesis was to investigate vascular dysfunction in RA and the relationship to markers of inflammation, and to assess whether intervention with NSAIDs, COX-2 inhibitors and TNFα-inhibitors has an effect on vascular function in RA. In a cross sectional study of 106 RA and control subjects pulse wave analysis (PWA) was performed. A subgroup of RA patients and controls had known coronary artery disease (CAD). Vascular measures were correlated with markers of inflammation (6).In a double blind placebo controlled trial, 37 RA patients were randomised to a two week course of COX-2 inhibitor, rofecoxib, NSAID, indomethacin or placebo. Flow mediated dilatation (FMD) and PWA were assessed before and after the two week treatment course (7). In a further intervention study 26 RA patients were randomised to TNFα-inhibitor Infliximab or placebo infusions. Vascular assessments included pulse wave velocity (PWV), PWA, carotid intima media-thickness (CIMT) and Carotid artery plaque (CAP). Follow up was to 56 weeks (8). Results from the cross sectional study confirmed that vascular function was impaired in RA and in the subgroup of patients with CAD when measured with PWA. Vascular function correlated with acute phase proteins when analysing the study group as a whole. In terms of short term intervention, COX inhibition with either rofecoxib or indomethacin did not significantly improve vascular function at two weeks as measured by FMD and PWA. Markers of inflammation also did not improve with these treatments. Post-hoc analysis of the infliximab intervention study using multivariate ANOVA modelling showed significant reduction in PWV over 56 weeks. RA disease activity and markers of inflammation also improved with this treatment. There was no change in PWA, CIMT or carotid plaques. In conclusion, patients with RA have impaired vascular function. This was independent of traditional CV risk factors but correlated with markers of inflammation. A short term intervention with a COX-2 inhibitor or NSAID did not improve vascular function at two weeks when measured with PWA in RA patients. Intervention with TNFα inhibitor improved PWV in RA patients at 56 weeks. These findings support the concept that chronic inflammation is associated with vascular dysfunction and this may relate at least in part to the increased CV risk in RA. Therapies effective in suppressing inflammation not only improve RA disease activity but also vascular function.