Includes a list of thesis related publications, reviews and thesis related abstracts, awards, book chapters and invited presentations (leaves vii-xii). / Includes bibliographical references (leaves 179-234). / xvii, 234 leaves : ill. (some col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / A systematic evaluation of magnetic resonance imaging and its use in the ex vivo and in vivo setting, in the aorta and coronary arteries in rabbit and porcine models, leading to the potential for human coronary atherosclerotic imaging. / Thesis (Ph.D.)--Adelaide University, Dept. of Medicine, 2001

Heart disease remains the leading cause of death globally, and prevalence has nearly doubled over the past three decades. It is estimated that up to 90% of cardiovascular events are preventable, but early detection and treatment is crucial. In this dissertation, we report on the optimization of the ultrasound-based cardiac strain imaging technique known as Myocardial Elastography (ME), a method for the detection of the most common and most lethal forms of heart disease: Coronary Artery Disease (CAD) which affects the major coronary arteries, and Coronary Microvascular Disease (CMD) which affects smaller coronary vessels. CAD has historically been the primary focus of clinical cardiac imaging, whereas CMD has been under-diagnosed due to a lack of awareness and challenges associated with imaging at the microvascular level. Ultrasound-based cardiac strain imaging has been shown capable of detecting functional changes due to CAD and may be effective in CMD detection, although the latter has not yet been sufficiently investigated. However, the diagnostic accuracy of strain imaging is reduced by noise from transcostal imaging, known as clutter, and by the limited lateral resolution of high framerate ultrasound. These factors preclude accurate strain imaging in up to 30% of patients. Myocardial elastography is a precise high framerate strain imaging technique that analyzes radiofrequency (RF) signals to quantify myocardial deformation. We hypothesize that ME can effectively image and diagnose the functional effects of CMD and CAD, and that novel beamforming and clutter-filtering techniques can improve ME imaging and strain estimation quality, thereby increasing diagnostic accuracy. To improve disease detection, Stress ME (S-ME) was proposed as a method to compare strain measurements at rest to strain during induced cardiac stress. A novel strain difference (Δ𝜺) metric was presented and investigated in a canine model of induced acute ischemia, as well as in a human CAD patient study with validation by myocardial perfusion imaging. In the canine model, flow-limiting stenosis was induced by partial ligation in N=2 canines, and stenosis was found to significantly reduce Δ𝜺 in the affected myocardial regions. In the clinical study, radial and circumferential ME strain and radial Δ𝜺 was measured in N=49 myocardial segments from 8 patients suspected to have ischemia or infarction due to CAD. The median Δ?, radial strain, and circumferential strain magnitudes were lowest in infarcted regions and highest in regions with normal perfusion, while measurements in ischemic regions fell in between. ROC analysis of radial strain metrics revealed that Δ𝜺 had the highest AUC for detecting ischemia (AUC=0.788 p<0.01) and infarction (AUC=0.792, p<0.05), followed by radial strain during stress (ischemia AUC=0.774 p<0.05, infarct AUC=0.758 p<0.05) while the AUC was lowest when considering only the radial strain at rest (ischemia AUC=0.52 p>0.05, infarct AUC=0.58 p>0.05). The results thus indicate that S-ME may improve detection of mild CAD cases that are functionally asymptomatic at rest. Despite these promising findings, accurate strain imaging remains hindered by clutter noise and poor image quality. Two complementary techniques were thus developed to improve image quality and strain estimation in high frame rate cardiac strain imaging; a novel Sliding Window implementation of the Minimum Variance beamformer (SWMV) was proposed to enhance speckle quality, while a spatiotemporal singular value decomposition filter (SVD) was developed to increase tissue visibility and contrast by suppressing static clutter signals using automated cutoff selection. SWMV and SVD were shown to effectively improve image quality in simulation studies and phantom imaging experiments. In vivo performance evaluation consisted of applying SWMV beamforming and SVD filtering techniques to a dataset of N=70 strain images from 13 patients suspected to have CAD. CCTA imaging was used for validation of strain estimation. Tracking was improved in 92% of cases with a median improvement of 15% in displacement estimation accuracy as evaluated by an intersection-over-union (IoU) metric. The proposed techniques also improve agreement with CCTA results; ROC analysis shows improved AUC with SWMV+SVD compared to DAS when comparing healthy regions to those with any degree of stenosis (AUC 0.64 vs 0.56) as well as when comparing healthy to severely stenosed regions (AUC 0.69 vs 0.60). The observed results point to significant improvement in strain estimation reliability due to SWMV beamforming combined with SVD processing. The final aim and the overarching goal of this work is a culmination of the previous sections for a clinical evaluation of ME as a diagnostic tool for CAD and CMD. In this clinical study, the enhanced ME technique utilizing SWMV and SVD filtering was applied to a cohort of N=201 patients with suspected coronary disease. All patients underwent invasive angiography or noninvasive cardiac imaging in the form of coronary computed tomography or nuclear stress testing. In addition, demographic information and patient clinical history were collected and accounted for in a multivariate statistical analysis. A K-nearest-neighbor (KNN) classifier was trained to distinguish between healthy and stenosed myocardial regions, and achieved an AUC of 0.91, with sensitivity of 86% and a specificity of 85% after training with 10-fold cross validation. CMD was also shown to significantly reduce regional strain measurements. This retrospective study identified the clinical factors which impact strain, and assessed the potential advantages of incorporating ME imaging to the existing clinical imaging pipeline for CAD and CMD diagnosis.

Coronary heart disease is the leading cause of premature death in the UK. Chest pain, the most common symptoms associated with this disease, accounts for 1% of all primary care consultations, 5% of visits to emergency departments, and up to 40% of emergency admissions to hospital. When people experience acute coronary symptoms such as chest pain, or other symptoms such as pain in the arms, back or shoulder pain and pain in the jaw and neck, we know that prompt diagnosis and treatment of heart disease can significantly reduce mortality. However, we also know that when people experience these symptoms they can wait sometime before seeking medical help. Part of the problem may be that people do not attribute their symptoms a serious problem such as heart disease. Whilst several campaigns have been aimed at the general population there is no information resource targeted at people who may be at risk of heart disease to help them understand and evaluate their symptoms and take prompt action. The overall aim of this thesis is to fill this gap by producing a piloted draft information resource which aims to help people to respond effectively to symptoms that might be attributable to heart disease for people at high risk of heart disease. Using focus group discussions and individual interviews with people who had experienced symptoms that might be attributable to heart disease or might be at high risk of heart disease experiential data about their response to symptoms were gathered. Participants were also asked their views on what an information resource should be like and their experiences and views formed the basis of the content of the first draft of the information resource. In making sense of their symptom the participants drew upon a range of past experiences and the experiences of others to help them; participants who experienced severe symptoms sought help quickly; those whose symptoms were mild or transient waited, in some cases a considerable time, before seeking help. Previous personal experience may be the factor that helped those who acted quickly. Whereas the experience of others, evident in many of the accounts of those who waited, may not be sufficient to help people interpret and make sense of their own symptom experiences. The information resource incorporated the experiences of people with symptoms that ended up being attributable to heart disease and included examples of the range of symptoms that can be encountered to illustrate the different ways in which heart disease can be manifested as well as information drawn from best practice resources in the management of heart disease. Participants in the original focus group discussions and interviews were asked to be involved in the development of the resource and seventeen agreed. The information resource went through three drafts; at each stage changes were made to incorporate respondent views; at the penultimate draft health professionals’ views were also sought and used to inform the final draft which is now ready for further evaluation.

Hyperventilation has been reported to cause false-positive ischemic shifts in the ST-segment of the electrocardiogram during exercise. These responses have been observed to occur at a higher incidence in females than males. Therefore, the purpose of this study was to determine the effects of the performance of pretest hyperventilation on ECG components that are suggestive of myocardial ischemia in females. A standard 12-lead Mason-Likar recording set was used including leads I, II, II, aVR, aVL, aVF, V₂, and V₅. Fifteen females comprised the subject pool for this study, which was screened on the basis of J-point depression in a preliminary exercise procedure. The fifteen subjects each performed two exercise sessions, one with no hyperventilation and the other with a preliminary hyperventilation. Statistically significant differences were found between the baseline and post-hyperventilation ECG (P<.05). Analysis of the results revealed no significant differences in J-junction depression, ST slope, and the ST integral between the two testing conditions. Hyperventilation did affect the ST responses of the ECG in these young adult females at baseline and its continued use in conjunction with graded exercise testing may help uncover ST-segment changes associated with false-positive exercise responses. Hyperventilation may be performed in young adult females in conjunction with GXTs without the liklihood of augmenting ST-segment shifts during the exercise. / Master of Science

This study sought to examine the exercise-induced ST-segment shifts, J₀ and J₆₀, attributable to ECG lead configuration, specifically to evaluate if ischemic changes are modified as a function of using the Mason-Likar lead system. Males (N=30) referred for diagnostic testing underwent a symptom-limited graded exercise test (SLGXT). ST-segment shifts, J₀ and J₆₀, measured as the difference from baseline to recovery minute one, were not significantly different in responses measured from two simultaneous complexes for lead V₅. In frontal lead II, differences were found in the ST-segment response at baseline vs. recovery minute one. All ST-segment shifts were computed as the difference between J_x obtained at resting baseline vs. the J_x obtained at the exercise measurement in the same posture. ST-segment shifts, J₀ and J₆₀, measured at peak-exercise vs. recovery minute one using the Mason-Likar lead system, revealed a significant difference according to the measurement recorded in both leads V₅ and II (p<.05). Comparisons of frequencies for clinically abnormal ST-segment shifts according to ECG lead configuration at recovery minute one when measured from peak-exercise using Mason-Likar were significant in only lead II (p<.05). Observation of the data suggest that the Mason-Likar lead system may affect the interpretation of ischemic ST-segment shifts in lead II. However, these results do not invalidate the interpretation of ischemic ST-segment shifts in lead V₅ using the Mason-Likar lead system. / Master of Science

published_or_final_version / Medicine / Doctoral / Doctor of Philosophy

The relationship between the PQ-segment slope on ST-segment depression during vigorous exercise was examined in 26 apparently healthy females between 18 and 26 years of age. Each subject performed 2 submaximal cycle ergometer exercise tolerance tests (trial A and trial B) on nonconsecutive days wherein the following variables, as delta scores, were measured; P-wave amplitude (microvolts), PQ-segment slope (uV!sec), and J-point at 0 and 60 msec (uV). Each variable was measured by both visual and computer averaging. The degree of reproducibility within and between trials differed for the visual and computer averaged measures. Generally higher reproducibility was found with computer averaging particularly within trial B (r =0.63-0.89, p<O.OI). Trial b served as a basis for assessment of PQ-segment slope effect on ST segment response. Computer analysis of frequency distribution for responses revealed a greater frequency of downsloping PQ-segment with clinically significant ST-segment depression (>50 uV) at both 0 and 60 msec after the J-point in lead II. However, there was a greater percentage (91%) of flat PQ-segment slopes with clinically significant ST-segment depression at J-point 0 msec in lead V5. These findings suggest possible influence of lead selection on the measurements of the PQ-segment slope and ST-segment. Implication of clinical application would be to use lead VS for diagnosing CHD and by measuring ST-segment depression at J-point 60 msec. However when screening exercise ECG tests in apparently healthy women use J-point at 0 msec. / Master of Science

Thesis (MCur)--Stellenbosch University, 2015. / ENGLISH ABSTRACT: Background: Coronary artery disease is a form of cardiovascular disease (CVD) which manifests itself in three ways: angina pectoris, acute coronary syndrome and cardiac death. Thirty-three people die daily of a myocardial infarction (cardiac death) and 7.5 million deaths annually are caused by CVD (51% from strokes and 45% from coronary artery disease) worldwide. Globally, the CVD death rate is a mere 4% compared to South Africa which has a 42% death rate. It is predicted that by the year 2030 there will be 25 million deaths annually from CVD, mainly in the form of strokes and heart disease. The WHO compared the death rates of high-income countries to those of low- and middle-income countries, like South Africa, and the results show that CVD deaths are declining in high-income countries but rapidly increasing in low- and middle-income countries. Although there are several risk prediction tools in use worldwide, to predict ischemic risk, South Africa does not use any of these tools. Current practice in South Africa to diagnose acute coronary syndrome is the use of a physical examination, ECG changes and positive serum cardiac maker levels. Internationally the same practice is used to diagnose acute coronary syndrome but risk assessment tools are used additionally to this practise because of limitations of the ECG and serum cardiac markers when it comes to NSTE-ACS. Objective: The aim of this study was to systematically appraise evidence on the accuracy of acute coronary syndrome risk prediction tools in adults. Methods: An extensive literature search of studies published in English was undertaken. Electronic databases searched were Cochrane Library, MEDLINE, Embase and CINAHL. Other sources were also searched, and cross-sectional studies, cohort studies and randomised controlled trials were reviewed. All articles were screened for methodological quality by two reviewers independently with the QUADAS-2 tool which is a standardised instrument. Data was extracted using an adapted Cochrane data extraction tool. Data was entered in Review Manager 5.2 software for analysis. Sensitivity and specificity was calculated for each risk score and an SROC curve was created. This curve was used to evaluate and compare the prediction accuracy of each test. Results: A total of five studies met the inclusion criteria of this review. Two HEART studies and three GRACE studies were included. In all, 9 092 patients participated in the selected studies. Estimates of sensitivity for the HEART risks score (two studies, 3268 participants) were 0,51 (95% CI 0,46 to 0,56) and 0,68 (95% CI 0,60 to 0,75); specificity for the HEART risks score was 0,90 (95% CI 0,88 to 0,91) and 0,92 (95% CI 0,90 to 0,94). Estimates of sensitivity for the GRACE risk score (three studies, 5824 participants) were 0,03 (95% CI0,01 to 0,05); 0,20 (95% CI 0,14 to 0,29) and 0,79 (95% CI 0,58 to 0,93). The specificity was 1,00 (95% CI 0,99 to 1,00); 0,97 (95% CI 0,95 to 0,98) and 0,78 (95% CI 0,73 to 0,82). On the SROC curve analysis, there was a trend for the GRACE risk score to perform better than the HEART risk score in predicting acute coronary syndrome in adults. Conclusion: Both risk scores showed that they had value in accurately predicting the presence of acute coronary syndrome in adults. The GRACE showed a positive trend towards better prediction ability than the HEART risk score. / AFRIKAANSE OPSOMMING: Agtergrond: Koronêre bloedvatsiekte is ‘n vorm van kardiovaskulêre siekte. Koronêre hartsiekte manifesteer in drie maniere: angina pectoris, akute koronêre sindroom en hartdood. Drie-en-dertig mense sterf daagliks aan ‘n miokardiale infarksie (hartdood). Daar is 7,5 miljoen sterftes jaarliks as gevolg van kardiovaskulêre siektes (51% deur beroertes en 45% as gevolg van koronêre hartsiektes) wêreldwyd. Globaal is die sterfte syfer as gevolg van koronêre vaskulêre siekte net 4% in vergelyking met Suid Afrika, wat ‘n 42% sterfte syfer het. Dit word voorspel dat teen die jaar 2030 daar 25 miljoen sterfgevalle jaarliks sal wees, meestal toegeskryf aan kardiovaskulêre siektes. Die hoof oorsaak van sterfgevalle sal toegeskryf word aan beroertes en hart siektes. Die WHO het die sterf gevalle van hoeinkoms lande vergelyk met die van lae- en middel-inkoms lande, soos Suid Afrika, en die resultate het bewys dat sterf gevalle as gevolg van kardiovaskulêre siekte is besig om te daal in hoe-inkoms lande maar dit is besig om skerp te styg in lae- en middel-inkoms lande. Daar is verskeie risiko-voorspelling instrumente wat wêreldwyd gebruik word om isgemiese risiko te voorspel, maar Suid Afrika gebruik geen van die risiko-voorspelling instrumente nie. Huidiglik word akute koronêre sindroom gediagnoseer met die gebruik van n fisiese ondersoek, EKG verandering en positiewe serum kardiale merkers. Internationaal word die selfde gebruik maar risiko-voorspelling instrumente word aditioneel by gebruik omdat daar limitasies is met EKG en serum kardiale merkers as dit by NSTE-ACS kom. Doelwit: Die doel van hierdie sisematiese literatuuroorsig was om stelselmatig die bewyse te evalueer oor die akkuraatheid van akute koronêre sindroom risiko-voorspelling instrumente vir volwassenes. Metodes: 'n Uitgebreide literatuursoektog van studies wat in Engels gepubliseer is was onderneem. Cochrane biblioteek, MEDLINE, Embase en CINAHL databases was deursoek. Ander bronne is ook deursoek. Die tiepe studies ingesluit was deurnsee-studies, kohortstudies en verewekansigde gekontroleerde studies. Alle artikels is onafhanklik vir die metodologiese kwaliteit gekeur deur twee beoordeelaars met die gebruik van die QUADAS-2 instrument, ‘n gestandaardiseerde instrument. ‘n Aangepaste Cochrane data instrument is gebruik om data te onttrek. Data is opgeneem in Review Manager 5.2 sagteware vir ontleding. Sensitiwiteit en spesifisiteit is bereken vir elke risiko instrument en ‘n SROC kurwe is geskep. Die SROC kurwe is gebruik om die akkuraatheid van voorspelling van elke instrument te evalueer en te toets. Resultate: Twee HEART studies en drie GRACE studies is ingesluit. In total was daar 9 092 patiente wat deelgeneeem het in die gekose studies. Skattings van sensitiwiteit vir die HEART risiko instrument (twee studies, 3268 deelnemers) was 0,51 (95% CI 0,47 to 0,56) en 0,68 (95% CI 0,60 to 0,75) spesifisiteit vir die HEART risiko instrument was 0,89 (95% CI 0,88 to 0,91) en 0,92 (95% CI 0,90 to 0,94). Skattings van sensitiwiteit vir die GRACE risiko instrument (drie studies, 5824 deelnemers) was 0,28 (95% CI 0,13 to 0,53); 0,20 (95% CI 0,14 to 0,29) en 0,79 (95% CI 0,58 to 0,93). Die spesifisiteit vir die GRACE risiko instrument was 0,97 (95% CI 0,95 to 0,99); 0,97 (95% CI 0,95 to 0,98) en 0,78 (95% CI 0,73 to 0,82). Met die SROC kurwe ontleding was daar ‘n tendens vir die GRACE risiko instrument om beter te vaar as die HEART risiko instrument in die voorspelling van akute koronêre sindroom in volwassenes. Gevolgtrekking: Altwee risiko instrumente toon aan dat albei instrumente van waarde is. Albei het die vermoë om die teenwoordigheid van akute koronêre sindroom in volwassenes te voorspel. Die GRACE toon ‘n positiewe tendens teenoor beter voorspelling vermoë as die HEART risiko instrument.