Heart failure is the leading cause of morbidity and mortality in the world. It is an incurable disease and most treatment strategies aim to treat the symptoms or slow the progression of the condition. Cardiac contractility is governed by calcium homeostasis within cardiac myocytes and is modulated by the sympathetic nervous system. Both mechanisms are detrimentally altered in heart failure. An important group of enzymes, phosphodiesterases, are fundamental to the sympathetic (beta-adrenergic) modulation of calcium cycling in cardiac myocytes. The selective inhibition of phosphodiesterase 5 (PDE5) has recently been considered as a potential therapy for heart failure; having beneficial effects in human and animal models of the disease. The present study employs a large animal model of tachypacing induced heart failure to test the effect of PDE5 inhibition on myocyte and whole heart contractility and beta-adrenergic function, to assess the molecular mechanisms by which PDE5 inhibition is beneficial to the failing myocardium. In initial experiments the PDE5 inhibitor sildenafil was applied acutely to voltage clamped ventricular myocytes from uninstrumented sheep. PDE5 inhibition reduced baseline L-type calcium current and systolic calcium transient amplitude, suggesting it is negatively inotropic. Furthermore, the positive inotropic effects of beta-adrenergic stimulation were somewhat reversed by acute PDE5 inhibition. Interestingly, such negative inotropic effects of acute PDE5 inhibition were not observed in failing ventricular myocytes, which have dysfunctional calcium homeostasis and beta-adrenergic reserve. When delivered chronically over 3 weeks to tachypaced animals, PDE5 inhibition restored and augmented the systolic calcium transient and beta-adrenergic responsiveness at both the whole heart and myocyte level. These effects were associated with changes to the expression and phosphorylation status of the proteins that control calcium homeostasis in left ventricular tissue. In vivo, PDE5 inhibition prolonged longevity and reduced the onset of clinical signs of heart failure in sheep, as well as arresting cardiac dilatation and wall thinning. Chronic PDE5 inhibition however had no effect on cardiac contractility or heart failure induced changes in cardiac electrophysiology. This study presents a novel mechanism by which PDE5 inhibition may be beneficial in a large animal model of heart failure by restoring calcium homeostasis and beta-adrenergic responsiveness. This study may have important implications for the management of heart failure in clinical practice.

Establishment of the biochemical and molecular nature of cardiac development is essential for us to understand the relationship between genetic and morphological aspects of heart formation. The molecular mechanisms that underly heart development are still not clearly defined. To address this issue we have used two approaches to identify genes involved in early chick cardiac development. Differential display previously conducted in our laboratory led to the identification of two gene fragments differentially expressed in the heart that are further described in this thesis. The full-length cDNA sequence of both eukaryotic translation initiation factor-2b (eIF-2b) and NADH cytochrome b5 reductase (b5R) were isolated using library screening. The upreglation of these genes during heart development is expected given the heart is the first functional organ to form in vertebrates and protein synthesis and cell metabolism at this stage of development is maximal. Limitations in the differential display approach led to the development and optimisation of a subtractive hybridisation approach for use with small amounts of cells or tissue. To focus on cardiac gene expression during the initial phases of heart development, subtractive hybridization was performed between the cardiogenic lateral plate mesoderm of Hamburger and Hamilton stage 4 embryos and the heart primordia of stage 9 embryos. Of the 87 independent clones identified by this procedure, 59 matched known sequences with high homology, 25 matched unknown expressed sequence tag (EST) sequences with high homology, and 3 did not match any known sequence on the database. Known genes isolated included those involved in transcription, translation, cell signalling, RNA processing, and energy production. Two of these genes, high mobility group phosphoprotein A2 (HMGA2) and C1-20C, an unknown gene, were chosen for further characterisation. The role of each gene in early chick heart development and indeed development in general, was addressed using techniques such as in situ hybridisation, transfection analysis, in ovo electroporation and RNAi. HMGA2 is a nuclear phosphoprotein commonly referred to as an architectural transcription factor due to its ability to modulate DNA conformation. In keeping with this function, HMGA2/GFP fusion protein was shown to localise to the nucleus and in particular, the nucleolus. In situ hybridisation analysis suggested a role for HMGA2 in heart and somite development. HMGA2 expression was first detected at HH stage 5 in the lateral plate mesoderm, a region synonymous with cells specified to the cardiac fate. HMGA2 was also strongly expressed in the presomitic segmental plate mesoderm and as somites developed from the segmental plate mesoderm, the expression of HMGA2 showed an increasingly more restricted domain corresponding to the level of maturation of the somite. Restriction of HMGA2 expression was first detected in the dorsal region of the epithelial somite, then the dorsomedial lip of the dermomyotome, and finally the migrating epaxial myotome cells. The novel intronless gene, C1-20C, predicts a protein of 148 amino acids containing a putative zinc finger binding domain and prenyl binding motif. Zinc binding assays showed that the zinc finger domain of C1-20C/MBP fusion protein bound over six times the quantity of zinc compared to MBP alone, although not in a 1:1 stoichiometric molar ratio. C1-20C/GFP fusion protein was shown to localise to as yet unidentified intracellular cytoplasmic vesicular compartments. These compartments did not colocalise with the endosome/lysosome pathway, aparently ruling out a role for C1-20C in protein trafficking, recycling or degradation. Expression of C1-20C in the chick embryo suggests a possible role in heart and notochord development and preliminary results using siRNA suggest that C1-20C is involved in normal heart looping.

In the present study the cognitive outcomes of cardiac surgery were examined in patients who did or did not develop delirium early post-operatively. The study expanded on previous research by investigating: (1) the relationship between delirium and functioning on specific cognitive domains; (2) the relationship between delirium and cognitive functioning after taking into account pre-existing cognitive impairment; and (3) the cognitive profile of delirium. The study employed a non-equivalent pre-test post-test design. Participants were 80 candidates for coronary artery graft replacement and/or heart valve repair or replacement operations who were 60 years of age or over. Participants underwent a neuropsychological assessment pre-operatively, daily assessments between post-operative days 2-5 for identification of delirium, and a follow-up neuropsychological assessment 12 weeks post-operation. Twenty-one participants met DSM-IV diagnostic criteria for delirium early post-operation. Participants who experienced delirium performed worse than participants who did not on one global cognitive measure and one specific cognitive domain at follow-up. However, this was likely due to the contribution of other factors such as age, years of schooling, pre-operative performance, and neurological events post-operation. There was no difference in the proportion of participants who did or did not develop delirium who met specified criteria for cognitive decline from pre-operation to follow-up. Significantly more participants who developed delirium, relative to those who did not, met criteria for pre-existing cognitive impairment. After taking into account pre-existing impairment and other potentially contributing variables, delirium was a significant predictor of performance on an attentional task at follow-up. There were no significant differences between the cognitive profiles of participants who did or did not develop delirium, at pre-operation or at follow-up. At both time points the profiles of these groups resembled the profile of a group of patients with vascular dementia. In conclusion, although participants who experienced delirium performed worse on certain cognitive domains, this appeared to be due to factors other than delirium. However, after taking pre-existing cognitive impairment, and other relevant variables into account, delirium adversely affected attentional performance. Delirium was associated with a vascular dementia profile, but this profile was not specific to delirium. Study findings have both theoretical and clinical implications. Consistent with the theoretical literature, the findings support impaired brain reserve as a risk factor for delirium, and the hypotheses that a combination of impaired brain reserve and events associated with delirium are responsible for subsequent cognitive performance. However, in the case of attention, events associated with delirium appear to be responsible for poorer performance, possibly due to the persistence of impaired attention, which is an essential feature of the delirium episode. A further theoretical implication is that individuals who experience delirium may be particularly vulnerable to developing vascular dementia, however, there needs to be further investigation of this risk in a non-cardiac surgery population. Clinically, study findings highlight the need to investigate possible cognitive impairment in individuals with cardiovascular disease, and in persons who experience delirium. When indicated, appropriate monitoring and/or treatment strategies should be employed to reduce the impact of cognitive deterioration.

This thesis is an epidemiological study of coronary heart disease (CHD) in New Zealand Maoris. Data from both cross-sectional and longitudinal surveys of defined populations are analysed. The prevalence and incidence of CHD are defined, the relationship between CHD and the standard risk factors are examined and the prognosis of CHD presented. Racial comparisons provide a valuable means of studing the epidemiology of CHD, as marked variation in the occurrence of CHD may occur in different races living in close proximity. Comparisons of New Zealand national mortality data do in fact indicate that the New Zealand Maori, especially the Maori female, is of relatively high risk of dying from CHD. This high risk status is in marked contrast to that of other Polynesian groups living more traditionally in which CHD is virtually unknown. Moreover, the high risk status of the New Zealand Maori would not have been predicted from a knowledge of their risk factor status. These two points, the high risk status of the Maori and their atypical risk factor pattern, provide the justification for this attempt to learn more about the occurrence and causation of CHD in New Zealand Maoris.

Thesis (M. Phil.)--University of Hong Kong, 2006. / Title proper from title frame. Also available in printed format.

Thesis (M.S.)--Eastern Illinois University. / Includes bibliographical references (leaves 67-71).

Thesis (Ph. D.)--Ohio State University, 2006. / Title from first page of PDF file. Includes bibliographical references (p. 48-54).

The newborn heart possesses a higher tolerance to ischemia in comparison to adult hearts. Post-ischemic interventions that increase energy production are beneficial for recovery. These data suggest that the newborn heart holds on a very tight energetic plasticity and may not be capable to effectively respond to increases in energetic demand. Congenital heart defects can lead to the development of cardiac hypertrophy and often require surgical intervention. Using an animal model of newborn hypertrophy and biventricular isolated working heart we confirm the metabolic profile of the newborn rabbit heart, in which fatty acid oxidation provides the vast majority of energy to the heart. Our findings show that when right ventricle load is added, the increasing energy requirements are met by increasing glucose oxidation rates. Our data generated by the isolated biventricular working heart model further supports the concept of the newborn heart in a state of deficient energy reserve.

Bad Heart Formation oolitic ironstone is the largest resources of iron in western Canada. During this study, 45 new sections from outcrop, trench and drill holes were mapped, and 325 samples were collected for petrographic and geochemical analysis. The objective of the first paper is to refine the previously published stratigraphic model based on the new data. The second paper deals with geochemistry and discuss genesis of ooids and source of iron in oolitic ironstone. The textures of the Bad Heart Formation ironstone suggest the ooids formed in-place in a relatively shallow, wave-agitated, oxygenated marine environment with repetitive growth of the ooids in water column. There are two possible source of iron in the ooids. Some geochemical data indicate it is continental sedimentary, but it is also possible that the iron sourced from sub-sea hydrothermal or meteoric vents, similar to recent iron deposits at Paint Pots in Kootenay National Park.

Aging is characterized by a progressive decline in cardiac function. A critical contributor to the age-related impairment in heart function is the loss of cardiac myocytes through ??apoptosis??, or programmed cell death. A dramatic increase in the rate of apoptosis has been reported with aging in the rat left ventricle. In contrast, exercise training not only improves cardiac function, but also reduces the risk of heart disease. However, the ability of exercise training to modulate apoptotic signaling and apoptosis in the aging heart remains unknown. Therefore, the purpose of this study was to determine the effects of exercise training on apoptotic signaling and apoptosis in the aging heart. We hypothesized that (1) aging would increase pro-apoptotic signaling and apoptosis in the rat left ventricle, and (2) exercise training would ameliorate upregulation of Bcl-2 family-driven apoptosis in the heart. Four and 25 month old Fischer-344 rats were assigned to four groups: young control (YC), young trained (YT), old control (OC), and old trained (OT). Exercise training groups ran on a treadmill for 60 min/day at 15 m/min (15˚ incline), 5 d/wk for 12 wk. Protein expression of Bax, Bcl-2, caspase-9, and cleaved caspase-3 was measured using Western immunoblot analysis. Apoptosis (DNA fragmentation) was assessed using a cell death detection ELISA. Bax levels in OC were dramatically higher (+176.0%) compared to YC. In contrast, exercise training resulted in a significant decrease (-53.4%) in Bax in OT compared to OC. Bcl-2 levels in OC were lower (-26.3%) compared to YC. Conversely, exercise training significantly increased Bcl-2 levels by 117.8% in OT compared to OC. Caspase-9 levels were higher (+98.7%) in OC than YC, while exercise training significantly reduced caspase-9 levels in YT (-52.6%) and OT (-76.9%), respectively. Aging resulted in a dramatic increase (+122.8%) in cleaved caspase-3 levels and a significant decrease (-32.9%) with exercise training. Finally, apoptosis (DNA fragmentation) significantly increased (+163.8%) with aging and decreased (-43.9%) with exercise training. These novel data indicate that aging increases pro-apoptotic signaling and apoptosis in the left ventricle, while exercise training is effective in diminishing pro-apoptotic signaling and apoptosis in the aging heart.