published_or_final_version / Medicine / Master / Master of Philosophy

Heart failure is associated with significant morbidity, mortality and economic cost. Over the past 30 years our understanding of the pathophysiology of heart failure has advanced greatly. However, morbidity and mortality remain high and further improvements in therapy are necessary. Pre-clinical data suggest that the novel peptide apelin, acting through the APJ receptor, has anti-hypertensive, vasodilator, diuretic and inotropic actions and an antagonistic relationship with angiotensin-II. These findings are of obvious interest in heart failure, particularly as plasma and myocardial apelin concentrations are reduced in patients with advanced heart failure. Consequently, it is hypothesised that upregulation of the apelin-APJ system may be of therapeutic value. The aims of this doctoral thesis were therefore to delineate the actions, mechanisms of action and relative efficacy of apelin; compare the arterial vasodilator action of apelin in health and heart failure; and examine the interactions of apelin with other key neurohormones in health and heart failure. This was achieved using wire myography and organ bath techniques in an array of animal and human blood vessels and in a validated rabbit model of post-myocardial infarction heart failure. Apelin is a modest nitric oxide and prostanoid dependent vasodilator at supra-physiological concentrations in small arteries. No such effect was noted in larger arteries or veins. This vasodilator action is abolished in heart failure, whilst response to acetylcholine is preserved suggesting an apelin-APJ specific abnormality in this syndrome. Apelin has an antagonistic relationship with endothelin-1 and synergistic relationship with B-type natriuretic peptide in normal small arteries. Again, these putative cardioprotective properties are lost in heart failure. These data suggest that the putative cardioprotective properties of apelin are lost in heart failure.

Treatments aimed at modifying cardiac substrate utilisation are designed to improve metabolic efficiency. In the fasting state, the heart mainly relies on fatty acid oxidation for its energy production. The heart can adapt to metabolise glucose, lactate and amino acids depending on the predominate milieu and demands placed upon it. A shift from fatty acid oxidation to carbohydrate oxidation leads to a lower oxygen consumption per unit of adenosine triphosphate produced. It is this concept of improving cardiac efficiency by a reduction in oxygen demand that underpins the use of metabolic manipulating agents as a therapeutic strategy in heart failure. Cardiac energy starvation is increasingly recognised as playing a central role in the pathophysiology of heart failure. Alterations in substrate utilisation thus underlie the hope that metabolic manipulating agents will be of benefit in heart failure of both ischaemic and non-ischaemic origin. This metabolic shift is achieved by promoting glucose utilisation and reducing the utilisation of fatty acids. This leads to a greater production of adenosine triphosphate per unit of oxygen consumed. With an ongoing demand for treatment options in ischaemic heart disease and the growing burden of chronic heart failure, new treatment modalities beyond contemporary therapy warrant consideration. This thesis aims to investigate the short term effects of metabolic manipulation on changes in cardiac energetic status, cardiac function, efficiency and substrate utilisation.

A percentage of either measured or predicted maximum heart rate is commonly used to prescribe and measure exercise intensity. However, maximum heart rate in athletes may be greater during competition or training than during laboratory exercise testing. Thus, the aim of the present investigation was to determine if endurance-trained runners train and compete at or above laboratory measures of ‘maximum’ heart rate. Maximum heart rates were measured utilising a treadmill graded exercise test (GXT) in a laboratory setting using 10 female and 10 male National Collegiate Athletic Association (NCAA) division 2 cross-country and distance event track athletes. Maximum training and competition heart rates were measured during a highintensity interval training day (TR HR) and during competition (COMP HR) at an NCAA meet. TR HR (207 ± 5.0 b·min-1; means ± SEM) and COMP HR (206 ± 4 b·min-1) were significantly (p < 0.05) higher than maximum heart rates obtained during the GXT (194 ± 2 b·min-1). The heart rate at the ventilatory threshold measured in the laboratory occurred at 83.3 ± 2.5% of the heart rate at VO2 max with no differences between the men and women. However, the heart rate at the ventilatory threshold measured in the laboratory was only 77% of the maximal COMP HR or TR HR. In order to optimize traininginduced adaptation, training intensity for NCAA division 2 distance event runners should not be based on laboratory assessment of maximum heart rate, but instead on maximum heart rate obtained either during training or during competition.

published_or_final_version / Zoology / Doctoral / Doctor of Philosophy

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Hyperlipidemia is prevalent following heart transplantation, and may play a role in the development of late graft atherosclerosis. The charts of 35 heart transplant recipients (n = 32 males and 3 females) were reviewed retrospectively up until three years post transplantation, to describe a time-course of hypercholesterolemia after transplantation, and to determine the mechanisms involved in its pathogenesis. All patients received prednisone, cyclosporine, and azathioprine for immunosuppression. A progressive rise in both serum cholesterol (2.4 $ pm$ 0.4 mmol/l, p $<$ 0.01), and body weight (8.4 $ pm$ 1.6 kg, p $<$ 0.01) were observed during the first 8 and 10 months respectively. Levels stabilized thereafter, remaining above pretransplant levels. Triglyceride, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol concentrations were all above normal limits following transplantation. Tapering of prednisone dose had a significant effect on serum cholesterol levels, whereas diet had a beneficial effect on body weight. A randomized, controlled, dietary intervention study then followed to further assess the effect of dietary intervention on minimizing or preventing post transplantation hyperlipidemia and weight gain. Five patients were counselled the Step One Lipid-Lowering diet, two patients were controls. All study patients demonstrated a lower overall increase in serum cholesterol levels than other transplant recipients. Reported nutritional intakes were similar between both groups. Increases in body weight were related to increases in body fat. Patients in the diet group demonstrated improvements in their level of nutrition knowledge, which correlated with lower serum cholesterol levels. Changes in serum cholesterol were also associated with appetite, hunger, perceived interest, perceived benefits, perceived barriers, and attitudes toward food. Changes in body weight were associated with appetite, hunger, perceived barriers, and stress. As