Medicine (St Vincent's) - Theses
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ItemThe contribution of the pulmonary circulation and cardiac function to exercise intolerance in people with diabetes( 2019)Diabetes mellitus (DM), and in particular type 2 DM (T2DM), is approaching epidemic proportions globally. Relative to people without diabetes, exercise performance is reduced by approximately 20% in T2DM subjects universally, whereas impairment in type 1 DM (T1DM) is less consistently reported. Risk of cardiovascular disease (CVD) is significantly elevated in both T1DM and T2DM, and thus emphasis is placed on cardiovascular constraints to exercise capacity, including subclinical cardiac dysfunction and the entity of diabetic cardiomyopathy (DMC). A clear bidirectional association between heart failure and T2DM exists, with numerous pathophysiological mechanisms identified in animal models. Longitudinal data suggests a low prevalence of heart failure in T1DM, on the other hand, which insinuates the pathological mechanisms thought to underpin DMC may be exclusive of chronic hyperglycemia which unifies the diagnosis of T1DM and T2DM. The pulmonary microvasculature is targeted in diabetes, meanwhile, and may be an under-appreciated contributor to exercise limitation. It is thought that the lungs are protected from deleterious effects of subclinical microvascular disease by virtue of their substantial size, although the ability to assess pulmonary microvascular function during exercise has been limited. This thesis assesses exercise performance (VO2peak) in people with T1DM and T2DM, evaluates the contribution of cardiac function and the pulmonary circulation using comprehensive traditional and novel echocardiographic analyses, and investigates the effect of phosphodiesterase type 5 (PDE5) inhibitor Sildenafil on exercise capacity. VO2peak is demonstrated to be impaired in only the T2DM cohort of the study group, and independently associated with sedentary lifestyle and reduced left ventricular end diastolic volume. Comprehensive resting and exercise echocardiographic measurements of biventricular systolic function and LV diastolic function, in addition to speckle-tracking global longitudinal strain and LV twist mechanics, are normal. The novel echocardiographic assessment of pulmonary microvascular function by measuring the pulmonary transit of agitated contrast (PTAC) identifies less PTAC (low-PTAC) in DM subjects, and associations with reduced RV function, higher pulmonary artery pressures, and lower exercise capacity. Finally, Sildenafil improves a number of central hemodynamic parameters but does not improve VO2peak. Results of this thesis support the argument that in the presence of impaired exercise performance and longstanding DM, subclinical cardiac dysfunction and DMC should not be universally anticipated. Diagnosis of pulmonary microvascular dysfunction using PTAC is feasible and readily accessible, and pulmonary microvascular disease is associated with reduced exercise capacity. Nonetheless, quantification of pulmonary microvascular disease remains imperfect, and the pulmonary vasodilator Sildenafil is ineffective in improving exercise performance presumably due to the mismatch between the pathophysiology thought to underpin diabetic lung disease and the more proximal smooth muscle vascular target of Sildenafil.
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ItemContractile dysfunction of the heart in early diabetes( 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.