Investigations into the safety of diagnostic ultrasound and mechanisms of therapeutic ultrasound have provided evidence of a number of cellular responses to ultrasound. These studies have mainly concentrated on cells in culture, while work on intact tissue employed mainly kHz ultrasound fields, although diagnostic and many therapeutic procedures are performed using MHz ultrasound. Vascular tissue is known to respond to a variety of physical and chemical signals, and so arteries were used as a model system in this thesis to study the effects of MHz ultrasound in vitro. Rings of equine carotid and lateral cecal mesenteric artery exhibited reversible, repeatable contraction on exposure to both pulsed and continuous wave 3.2 MHz ultrasound at acoustic powers up to 145 mW. Wall stress increased by up to 1.5% in carotid arteries and up to 2% in mesenteric arteries during exposure, and returned to basal levels after approximately 10 minutes. Contraction was endothelium independent, and was not affected by changes in the pulsing regime. The magnitude of contraction was dependent on the acoustic power, and the change in wall stress increased with increasing acoustic power in a linear fashion. The acoustic power dependence suggested the response was thermally mediated and this was confirmed by investigation of the response of arteries to non ultrasound generated heating, which also induced contraction. The effects of ultrasound and heating were also investigated in 1st order branches of the lateral cecal artery, as a model of a small artery. No response was observed in either case. In order to determine the cellular basis of the response of carotid and mesenteric arteries, the involvement of potassium ion channels in the response was investigated using a potassium channel blocker. The response of arteries to ultrasound was increased by inhibition of inward-rectifier potassium channels, which would otherwise help to return the cell membrane potential to the normal level. The change in wall stress was increased by 42% on average, confirming the involvement of these channels in the response. Contraction of arteries is mediated by an increase in intracellular calcium. The ion channel activity during non ultrasound generated heating was examined further by observation of intracellular calcium concentration using a fluorescent calcium sensitive dye. Increases in intracellular calcium were observed in carotid and large mesenteric arteries, which confirmed the thermal influence on ion channel function in these vessels. No such effect was observed in the smaller vessels.

Tight regulation of cephalic blood circulation is critical under normal physiological conditions, and dysregulation of blood flow to the head occurs in pathophysiological situations such as stroke and migraine headache. The facial artery is an extracranial artery which is one of branches from the external carotid artery territory and its extracranial position indicates its importance in regulating head hemodynamics. Transient receptor potential vanniloid type 1 (TRPV1) is a cation channel permeable to Ca2+ and Na+. Intracellular Ca2+ increase causes vasoconstriction. A previous study indicated the presence of TRPV1 in smooth muscle cells in the facial artery. Protein kinase C (PKC) is found to sensitize TRPV1 channels in neurons. Our lab's preliminary data suggested PKC modulates TRPV1 in the middle meningeal artery. Serotonin (5-HT) is an endogenous vasoconstrictor, and the 5-HT2 receptor is a Gq-protein-coupled receptor that activates PKC. In the present study, we found that 5-HT caused facial artery constriction. Thus, we studied whether TRPV1 channel acting as a Ca2+ entry channel is involved in 5-HT induced facial artery constriction. We used a pressurized arteriography technique to examine the artery diameter. The results indicate that 1) TRPV1 antagonist blunted 30 nM 5-HT-induced mouse facial artery constriction. 5-HT constriction on the facial artery from TRPV1 knock out mice was significantly blunted compared to the constriction on the facial artery from wild type mice; 2) PKC, which is a downstream signaling molecule of 5-HT2 receptor, is involved in capsaicin (TRPV1 agonist)-induced facial artery constriction; 3) 5-HT-induced facial artery constriction is mediated mostly by activation of 5-HT1 and 5-HT2 receptors; 4) 5-HT2 but not 5-HT1 receptor is involved in 5-HT-induced facial artery constriction via opening of TRPV1 channels; 5) PKC may be involved in 5-HT-induced facial artery constriction; 6) The L-type-voltage-dependent Ca2+ channel is involved in 5-HT-induced facial artery constriction. We conclude that activation of TRPV1 channel contributes to serotonin-induced 5-HT2 receptor-mediated constriction of the mouse facial artery.

Patients that have suffered from a heart attack, has a condition called coronary artery disease. This condition is partly inherited, by lifestyle choices such as diet, smoking and exercise account for as much as 80 % of the disease progression and outcome. Today a great majority of patients with coronary artery disease choose not to participate in an exercise-based rehabilitation programme after an event, even though exercise has shown to reduce mortality rates by more than 25 %. What if we could encourage patients with coronary artery disease to engage in exercise-based rehabilitation treatment outside a hospital environment?

Ph.D., Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand, 2008. / In many developing countries with advanced stages of the nutrition transition, the burden of coronary artery disease (CAD) has shifted from the rich to the poor. Much of this transition is caused by changes in lifestyle, in particular: dietary changes, an increase in weight and obesity, a decrease in physical activity, high levels of stress, and increasing tobacco and alcohol consumption. However, we have come to appreciate a prominent role for inflammation in atherosclerosis and its complications. Globalization, urbanization and Westernization of lifestyle will increase the socioeconomic burden posed by non-communicable diseases in middle-to-low-income countries. In South Africa, it is mainly the African population that is experiencing rapid urbanization and the nutrition transition. Reliable ischaemic heart disease (IHD) mortality data are not available for the black population of South Africa. The purpose of this thesis was: to determine whether factors such as inflammation, postprandial lipaemia and hyperglycaemia are important determinants in black patients with documented CAD (with no previous known history of diabetes mellitus) and their age matched controls; to assess the prevalence of the metabolic syndrome (MS) in black patients and abnormal glucose regulation on black patients with CAD; and to compare the metabolic syndrome prevalence rates using the National Cholesterol Education Program Adult Treatment III (NCEP: ATP III) and International Diabetes Federation (IDF) definitions. Socio-economic status, anthropometric data, glucometabolic variables, LDL particles and MS prevalence rates were measured using 40 patients and 20 controls. The patients were selected consecutively on the basis of a coronary angiogram performed during the preceding 24 months. All subjects had significant CAD, which was defined as more than 50% lesions in one or more major coronary arteries. Subjects with severe hypercholesterolaemia, defined as an untreated total cholesterol level over 7.5 mmol/l, were excluded from the study. Those subjects with diabetes mellitus or HIV/AIDS were excluded from the study. Paper 1, titled ‘Metabolic syndrome, undiagnosed diabetes mellitus and insulin resistance are highly prevalent in urbanized South African blacks with coronary artery disease’, demonstrated a high prevalence of MS in black patients with established CAD. To our knowledge, this is the first report from South Africa that documents the prevalence of the syndrome in black patients with CAD. Almost all of our patients had previously diagnosed hypertension (95%). The second most frequent risk factor was an elevated glucose concentration, which was seen in half the patient cohort. The importance of obesity, particularly abdominal obesity expressed as waist circumference (WC), is well documented as a risk factor for MS. An unexpected outcome of our study was that half of the patients had abnormal glucose regulation, despite the exclusion of previously diagnosed DM. This high prevalence was revealed by the oral glucose tolerance test (OGTT). Paper 2 compares the MS prevalence estimates, as defined by NCEP: ATP III and IDF, amongst urbanized black South Africans with CAD. The IDF proposed a single unifying definition in 2005, as different definitions used different sets of criteria; this led to confusing and inconsistent estimations of MS prevalence. The new definition standardizes the criteria for the diagnosis of MS and offers a fresh assessment of the syndrome. The main findings that arose from the study were that both definitions generated similar prevalence estimates of MS and the two definitions similarly identified the presence or absence of MS in more than 80% of patients. This study demonstrated that postprandial lipaemia and hyperglycemia were common in black CAD patients. Small dense LDL particles were highly associated with CAD. Fasting triglyceride concentrations was the strongest determinant. Prolonged exposure of the endothelium to TG–rich atherogenic remnant particles might be the reason why postprandial increases in TG account for greater CAD risk. Paper 3 assessed postprandial lipaemia in black CAD patients with and without metabolic syndrome. This study was the first to contribute information about postprandial lipaemia and hyperglycaemia in urbanized South African blacks with CAD. Fasting lipid profiles and postprandial responses to the oral fat load were similar in patients with and without metabolic syndrome. A possible explanation might be that because patients in both groups had established CAD, they exhibited some of the underlying features of CAD, such as atherogenic dyslipidaemia. The main finding was that postprandial lipaemia was common in black CAD patients, including patients with metabolic syndrome. Fasting triglycerides concentration was the strongest determinant. Small, dense LDL particles were highly associated with CAD. Paper 4 reports on the assessment of postprandial hyperglycaemia in urbanized blacks with and without CAD. Results showed that glucose AUC was significantly higher in the patients than in control subjects and 120 min. glucose, followed by 0 min. glucose concentration, were the strongest determinants of postprandial hyperglycaemia. Our study demonstrated that as glucose tolerance declined across the normal glucose tolerance, impaired glucose tolerance and diabetes mellitus categories, peak glucose concentrations occurred later in the oral glucose tolerance test; insulin and proinsulin responses were also delayed. A comparison between CAD patients and control subjects drawn from the same ethnic population verified that abnormal glucose tolerance and insulin resistance were more prevalent in the patients with CAD. Paper 5 aimed at investigating whether carotid intima-media thickness (CIMT) is a predictor of CAD in South African black patients. The results showed that CIMT correlated with evidence of angiographically proven CAD. The findings of this study need to be considered within the context of its limitations, i.e. the low number of women and some bias towards only hospital referred CAD patients. It was not our intention to recruit more men than women, but because CAD is more prevalent in men, the majority of participants happened to be male. Performance of the OGTT and hyperinsulinaemic euglycaemic clamp technique is time consuming and requires considerable laboratory resources; therefore a relatively small number of patients and control subjects were studied. These limitations do not detract from the overall conclusions. Paper 6 evaluated markers of inflammation in black CAD patients, some of whom had MS. Leptin was the only marker that increased with additional MS criteria. Elevated hs- CRP concentrations indicated an inflammatory state in CAD patients. Association of leptin with BMI, waist circumference (WC) and hs-CRP revealed a close link with MS, obesity and inflammation in urban black South African CAD patients. Paper 7 investigated the role of diet, socio-demographics and physical activity in a black South African population with CAD, compared to a healthy control group. While diet is known to be affected by urbanisation, differences in dietary intake were observed between the two urban groups, despite the similarity in their socio-demographic profile. The study highlighted the clinical relevance of MS, its likely impact on morbidity and mortality, and that its identification is, therefore, important in risk assessment of patients with CAD. Increasing recognition of MS is, therefore, an initial step in addressing the metabolic problems associated with the syndrome. Furthermore, it was shown that a preponderance of small, dense LDL particles was highly associated with CAD in black patients. Although CAD prevalence is still low at this stage, it is likely to increase rapidly among urban dwellers as they adopt a Western lifestyle.

vii, 169 leaves : / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Surgery, 1975

published_or_final_version / Anatomy / Master / Master of Medical Sciences

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