Thesis (M.Med.Sc.)--University of Hong Kong, 2000. / Includes bibliographical references. Also available in print.

Thesis--Wisconsin. / Vita. Includes bibliographical references (leaves 111-117).

Thesis (MD.(Internal Medicine)--Faculty of Health Sciences)-University of Pretoria, 2004. / Summary in English and Afrikaans. Includes bibliographical references. Adobe Acrobat reader needed to open files.

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A recent proposal is that the alpha₁-adrenoceptor may mediate the arrhythmogenic effect of catecholamines during acute myocardial ischaernia. The purpose of this thesis was to explore the role of alpha₁ and alpha₂-adrenoceptor stimulation on vulnerability to ventricular fibrillation in the norrnoxic rat ventricular myocardium and further to evaluate the possible underlying cellular mechanism. The model used was the isolated perfused rat heart (Langendorff technique) in which ventricular fibrillation was electrically induced. The amount of current required to produce ventricular fibrillation was measured as the ventricular fibrillation threshold. Alpha₁-adrenoceptor stirnμlation with methoxamine to 10⁻⁶M to 10⁻⁵M increased the vulnerability to ventricular fibrillation. The arrhythmogenic effect of methoxamine could not be attributed to beta-adrenoceptor stimulation as it occurred in the setting of the beta-adrenoceptor antagonist agent, atenolol; furthermore no accumulation of cyclic AMP, the proposed arrhythmogenic second messenger of beta-adrenoceptor stimulation, occurred. Similarly no alteration in heart rate, coronary flow rate or myocardial high energy phosphate content accompanied the arrhythrnogenic effect of methoxamine. The QT interval increased with alpha₁-adrenoceptor stimulation, this being an indirect index of prolongation of the action potential duration. The arrhythmogenic action of methoxamine was associated with a positive inotropic effect. Prazosin 10⁻⁸M (an alpha₁-adrenoceptor antagonist agent) produced a tenfold displacement to the right of the log concentration response curve of the positive inotropic effect of methoxamine. Prazosin 10⁻⁸M prevented the methoxamine induced fall in ventricular fibrillation threshold. Alpha₂-adrenoceptor stimulation with B-HT 920 and B-HT 933 (azepexole), in the presence of the beta-adrenoceptor antagonist agent atenolol, did not alter the vulnerability to ventricular fibrillation. Alpha₂-adrenoceptor stimulation produced no alteration in heart rate, coronary flow rate or metabolic status. We next explored the possible mechanism underlying the arrhythmogenic effect of methoxamine. Alpha₁-adrenoceptor stimulation enhances transsarcolemmal calcium ion influx and may induce sarcoplasmic reticulum calcium release. To assess the role of transsarcolemmal calcium movement in alpha₁-adrenoceptor mediated effects experiments were undertaken with nisoldipine and low extracellular calcium. To evaluate the role of sarcoplasmic reticulum calcium release, experiments were undertaken with ryanodine (an agent reputed to inhibit sarcoplasmic reticulum calcium release without effecting the slow inward current). Nisoldipine 10⁻⁸M, reducing extracellular calcium (2.5 mM to 1.25 mM) and ryanodine 10⁻⁹M to 10⁻⁸M, prevented the arrhythmogenic and positive inotropic effect of methoxamine. Heart rate, metabolic status and cyclic AMP levels we're unchanged with these procedures. The mechanism underlying the arrhythmogenic action of alpha₁-adrenoceptor stimulation might be an increase in cytosolic calcium concentration. This increase may be secondary to (i) an enhanced transsarcolemmal calcium influx or (ii) an increase in the phasic release of calcium from the sarcoplasmic reticulum.

published_or_final_version / Medicine / Master / Doctor of Medicine

Background: Recent studies have revealed an association between genetic variants at the ADAMTS7 (a disintegrin-like and metalloprotease with thrombospondin type 1 motif, 7) locus and susceptibility to coronary artery disease (CAD). ADAMTS-7 has been reported to facilitate vascular smooth muscle cell (VSMC) migration and promote neointima formation. We sought to study the functional mechanisms underlying this relationship and to further investigate the role of ADAMTS-7 in atherosclerosis. Methods and Results: In vitro assays showed that the CAD-associated non-synonymous single nucleotide polymorphism rs3825807, which results in a serine to proline (Ser-to- Pro) substitution at residue 214 in the ADAMTS-7 pro-domain, affected ADAMTS-7 prodomain cleavage. Immunohistochemical analyses showed that ADAMTS-7 localised to vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) in human coronary and carotid atherosclerotic plaques. Cell migration assays demonstrated that VSMCs and ECs from individuals who were homozygous for the adenine (A) allele (encoding the Ser214 isoform) had increased migratory ability compared with cells from individuals who were homozygous for the G allele (encoding the Pro214 isoform). Western blot analyses revealed that media conditioned by VSMCs of the A/A genotype contained more cleaved ADAMTS-7 pro-domain and more of the cleaved form of thrombospondin-5 (TSP-5, an ADAMTS-7 substrate that had been shown to be produced by VSMCs and inhibit VSMC migration). In in vitro angiogenesis assays, ECs of the A/A genotype exhibited increased capillary-like network formation. ADAMTS-7 over-expression in ECs by transfection of an ADAMTS7-214Ser expressing plasmid significantly accelerated EC migration and in vitro angiogenesis, whereas ADAMTS-7 knockdown by shRNA had opposite effects. Preliminary proteomics analyses of conditioned media of ECs overexpressing ADAMTS-7 and ECs with ADAMTS-7 knockdown indicated that ADAMTS- 7 can cleave thrombospondin-1 (TSP-1), a well-recognised angiogenesis inhibitor. Conclusion: The results of this study indicate that rs3825807 has a functional effect on ADAMTS-7 maturation, TSP-5 cleavage, VSMC and EC migration, and angiogenesis. As VSMC migration and angiogenesis play important roles in atherosclerosis, these results provide a mechanistic explanation for the association between rs3825807 and CAD.

Acute coronary syndrome (ACS), the acute manifestation of coronary heart disease (CHD), is the leading cardiovascular cause of mortality and morbidity globally, and represents one of the most common causes of acute medical admissions to Australian hospitals. Following medical and/or surgical management of ACS, lifestyle modification to reduce the underlying risk factors that contribute to the progression of the disease remains vital. Cardiac rehabilitation (CR) has been widely accepted as an intervention that can reduce mortality and modify risk factors for subsequent coronary events and cardiovascular disease. While the benefits of cardiac rehabilitation programs have been demonstrated, participation and adherence to these programs remain low for various reasons, particularly among patients whose treatment includes revascularisation with percutaneous coronary intervention. This method of revascularisation has become increasingly common due its immediate success, rapid procedural technique, short hospital stay and early return to work for patients of working age. The aim of this study was to develop and test the feasibility of an evidence-based health-related lifestyle management program for risk factor modification in patients with ACS undergoing percutaneous coronary intervention. Four distinct yet interrelated studies were undertaken as part of the Development and evaluation of a Health-related Lifestyle self-Management (HeLM) intervention for patients with ACS Project. Three of these studies informed the development of the HeLM intervention, which was based on the principles of chronic disease self-management and evidence-based practice that included best evidence from the literature, clinical expertise and patient preferences. The first study was a systematic review of the literature to identify the best available evidence of the effect of brief interventions for lifestyle modification in patients with CHD. Findings from the 17 trials included in the systematic review, although inconclusive suggest that brief structured interventions can have beneficial effects on risk factor modification and consequently on progression of CHD. The second study was a qualitative interview of CR coordinators to identify from their clinical expertise the influence of the Reducing Risk in Heart Disease guidelines on practice: the Implementation of the Cardiac Evidence-Based Reducing Risk in Heart Disease Guidelines (ICEBRG) study. Findings from this study indicated limited implementation of the guidelines due to various barriers relating to health services, CR programs, professional practice and the patient and their families. Despite these barriers, it was evident that CR coordinators were striving to overcome these odds and provide evidence-based care. The third study undertaken to identify patient preferences for CR was the Follow-up After percutaneous Coronary Treatment (FACT) Study. The findings indicated that although the majority of the participants had two or more risk factors, they lacked knowledge of the link between risk factors and CHD, and less than a third had attended CR. The main reasons for nonattendance included timing, distance to travel, length of program, work commitments and lack of motivation to attend the programs. Their suggestions for improvement included telephone follow-up and flexibility of the CR programs. This study also informed the development of a tool that can be used by clinicians to flag patients who are unlikely to attend traditional CR. Identification of these people will allow alternate strategies to reduce risk factors to be tailored to their needs. The findings from these three studies were used to develop the HeLM intervention. The final study was undertaken to assess the feasibility of the HeLM intervention that was based on evidence compared to standard treatment for promoting lifestyle modification. This study was undertaken in 51 participants who were followed up two weeks following the completion of the intervention. The findings demonstrated that patients found the information beneficial and were pleased to receive it in their homes. The telephone support was also extremely well received. The study enabled the program and the process for implementation to be refined and indicated that a large multicentre trial would be feasible. The HeLM may be a strategy that could reach patients who have thus far eluded traditional CR programs and support them to make the necessary lifestyle changes. It may also be an adjunct to traditional CR and have a synergistic effect in facilitating health-promoting behaviours in CHD patients. Studies of interventions for risk factor modification in participants with CHD require longer term follow-up to assess the effect of the intervention in the sustainability of behaviour modification. Further research is necessary to evaluate the long-term effects as well as the cost effectiveness of the intervention. / Doctor of Philosophy (PhD)

Thesis (Ph. D.)--University of Hong Kong, 2007. / Title proper from title frame. Also available in printed format.