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Large artery stiffness is predictive of adverse cardiovascular events and all cause mortality. Artery structure and function are determinants of artery stiffness. This thesis presents a series of in-vivo experimental studies of effect of structural and functional changes on large artery stiffness. Improved analysis methods were developed for measurement of arterial stiffness indexes, Pulse Wave Velocity (PWV) and pressure wave re ection. These were applied in studies of acute in ammation, active and passive changes in systemic pressures, aortic elastic laminae defects, and aortic calcification in rats using a novel, high fidelity, dual pressure sensing technique of measuring aortic rat PWV. Findings indicated that acute in ammation does not increase large artery stiffness, and that localised effects altering arterial structure do not manifest in in-vivo changes in large artery stiffness. The functional component of stiffness was investigated using graded systemic infusion of vasoconstrictor agents (angiotensin-II, noradrenaline, and Endothelin-1 (ET-1)) in the in-vivo ovine iliac artery. There was a markedly greater dose dependency of pressure independent change in PWV (angiotensin-II) compared to direct endothelial effects (ET-1), although blocking of ET-1 receptors produced marked changes in iliac blood ow. A similar experiment in the human iliac artery found that the B-antagonist and nitric oxide (NO) donor, x Structural and functional effects on large artery stiffness nebivolol, potentially causes a decrease in regional functional stiffness. An additional study in human subjects directly measured the decrease in forearm arterial stiffness during reactive hyperaemia following different periods of ischaemia. The findings precluded the use of this method in measuring brachial artery structural stiffness with maximal smooth muscle relaxation. Increasing periods of ischaemia had a bi-phasic relationship with changes in arterial stiffness, the first phase linked to endogenous nitric oxide release. This finding is of importance in the clinical quantification of endothelial dysfunction. These findings in basic research of arterial haemodynamics provide new quantitative contributions to the in-vivo experimental investigation of the aetiology of large artery stiffness related to structure and function of endothelial and medial wall properties. This can lead to potential clinical applications and techniques for assessment of cardiovascular risk.

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The work presented includes over thirty peer reviewed published manuscripts based on studies undertaken during my surgical career. As Principal Investigator, I led the study conception/design/data acquisition/analysis/interpretation and was involved with writing the final drafts of all manuscripts prior to their formal submission to high impact factor peer-reviewed specialist journals. The thesis is divided into subsections reflecting my development and different interests within surgery. The subsections start with my learning basic research principles, moving onto clinical problem solving in general surgical dilemmas, followed by a collection of papers in my subspecialty of vascular surgery. The work culminates with a group of papers focused on aneurysmal disease, specifically, abdominal aortic aneurysms (AAA), the clinical impact of which has had a bearing on the introduction of a National AAA Screening Program in Wales in 2013. I conclude these sections with a collection of papers that reflect my long term commitment to surgical training both at regional level (as Secretary and Deputy Chairman to the Higher Surgical Training Committee and Chairman of the Basic Surgical Training Committee) and national level including my involvement with the Four Royal Colleges of Surgeons for the Intercollegiate Examinations in General Surgery. This examination is undertaken at completion of junior surgical training and used to confirm a doctor's competence for safe independent practice as a consultant. In conclusion, over forty years of academic research during my career as a vascular surgeon has provided unique insight into the pathophysiology, treatment and ultimately prevention of artherosclerotic disease. These findings have improved health policies in Wales and significantly reduced patient morbidity and mortality.

Peripheral arterial disease (PAD) affects approximately 200 million individuals worldwide. It is characterized by a reduction in blood flow to the lower extremities due to atherosclerosis. This can result in leg pain, tissue loss, and ultimately amputation. Revascularization procedures aim to restore blood flow, but up to 50% of patients require another intervention within a year. Revascularization monitoring and early detection of failure are crucial in preventing limb loss and adverse cardiovascular events. However, current evaluation methods do not directly measure perfusion and are limited in a significant segment of PAD patients, such as those with diabetes and renal insufficiency. Diffuse optical imaging (DOI) techniques are promising tools to overcome these limitations. Employing near-infrared light, they are non-invasive, non-ionizing, contrast-free, and cost-effective methods that are sensitive to hemodynamic parameters such as changes in oxy-, deoxy-, and total hemoglobin concentration, making DOI ideal for revascularization monitoring. In this dissertation, I investigate and develop DOI systems for the purpose of monitoring lower extremity revascularization procedures in PAD patients. We utilize a contact-based diffuse optical spectroscopy (DOS) system to monitor localized foot perfusion in an ongoing clinical study of 100 patients undergoing lower extremity angiography. I demonstrate the utility of DOS measurements to provide valuable insights into revascularization related hemodynamic remodeling and to predict revascularization success. Furthermore, I also develop a clinic friendly contact-free diffuse optical tomography (DOT) system that is better-suited for PAD patients with ulcers. I show that this system can provide spatial maps of perfusion within the foot. Collectively, this work establishes diffuse optical imaging as a valuable imaging modality for the evaluation of lower extremity perfusion.

Includes bibliographical references. / 3 v. : / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / A selection of research papers, reviews, books and book chapters ... considered representative of the works by the author over the years 1958-1993. / Thesis (D.Sc.)--University of Adelaide, Dept. of Pathology, 1995

published_or_final_version / abstract / toc / Medicine / Master / Doctor of Medicine

The purpose of this study was to determine whether graded exercise test (GXT) variables known to have prognostic importance in the setting of severe-moderate coronary artery disease (CAD) and early post-myocardial infarction (MI) patients can also differentiate which physically active male patients with lesser disease and/or old MIs (undergoing serial GXT evaluation and an exercise maintenance program) will have a serious cardiac event, i.e., MI, coronary artery bypass surgery (CABG), or death. Data were obtained at two cardiac rehabilitation sites from three GXT results in 14 paired cardiac event (CE) and nonevent (NE) group subjects based on peak estimated oxygen consumption (VO_2estpk). Comparisons were also made with seven of these 14 paired group subjects for whom peak measured oxygen consumption (VO_2pk) were available. Statistical analyses were done on certain continuously-scaled, ordinally-scaled, and dichotomized dependent variables from selected GXTs. The continuously scaled dependent measures included VO_2estpk peak heart rate (HR_pk), resting heart rate (HR_rest), peak rise in exercise heart rate (HR_diff), peak systolic blood pressure (SBP_pk), rise in exercise systolic blood pressure (SBP_diff) and peak rate pressure product (RPB_pk), whereas, the ordinally-scaled dependent measures included functional aerobic impairment (FAI) and cardiac rehabilitation potential (CRP). For the dichotomized variables, ischemic ST-segment deviation at peak exercise (ischemic ST_dev} I exercise-induced ventricular dysrhythmias (VENT_dys) and exercise-induced chest pain were selected. Hotelling's T² test was utilized for analysis of the continuously- and ordinally-scaled dependent measures, whereas chi-square test was used for the dichotomized variables. There was a significant difference (F = 3.53; df = 3,11; p = .05) found between the paired CE-NE groups at and within each GXT time period for HR_diff in the 14 paired groups. Statistical analyses revealed no significant differences for any other variables in either the 14 paired and 7 paired groups. The small sample size limited the potential for statistical testing of the results in this study. However, the findings do appear to support that a poor chronotropic response indicated by HR_diff may have prognostic importance for those active CAD participants in supervised exercise maintenance programs who are at risk of a future cardiac event, i.e. MI, CABG, or death. / Master of Science