As cardiovascular disease remains the global leading cause of death, there is an urgent need to study the pathophysiology of the heart and to effectively evaluate cardioprotective drugs. Due to the difficulty in studying the human heart in vivo and sourcing human heart tissues, induced pluripotent stem cells (iPSCs) have provided a promising alternative for modeling cardiac diseases and evaluating candidate drugs. In recent years, computational methods, including machine learning, have given rise to a new class of tools to evaluate cardiac function more rapidly and comprehensively. In this dissertation, I develop and apply computational tools to probe the function of human iPSC-derived cardiac models (Aim 1), apply machine learning methods in the context of cardiomyocyte disease phenotyping and cardioactive drug profiling (Aim 2), and develop a pipeline for deep learning-driven cardiac fibroblast phenotypic drug discovery (Aim 3).

Conclusion 1. The results of the research partly supported hypothesis 1a. There was a significant reduction in both endothelium-dependent arterial relaxation following a surgical menopause. The results of the research partly supported hypothesis 1b. There was a significant reduction in endothelium-dependent arterial relaxation but no significant effect on endothelium-independent arterial relaxation. / Conclusion 2. The results of the research partly supported hypothesis 2a. The addition of unopposed oestrogen significantly improved endothelium-dependent but not endothelium-independent arterial relaxation. The results of the research supported hypothesis 2b. The addition of oestradiol combined with progestogen (norethisterone acetate) reversed the reduction in arterial relaxation caused by a surgical menopause. The results of the research partly supported hypothesis 2c. The addition of tibolone reversed the reduction endothelium-dependent but not endothelium-independent arterial relaxation. The results of the research partly supported hypothesis 2d. The addition of oestradiol combined with a progestogen (norethisterone acetate) reversed the reduction in endothelium-dependent but not endothelium-independent arterial relaxation. / Conclusion 3. The results of the research partly supported hypothesis 3a. Endothelium-dependent arterial relaxation but no endothelium-independent arterial relaxation was improved after the addition of menopausal hormone therapy using oestrogen combined with a progestogen in a continuous manner. The results of the research did not support hypothesis 3b. Neither endothelium-dependent arterial relaxation nor the endothelium-independent arterial relaxation was improved by cyclical menopausal HT. / Conclusion 4. The results of the research did not support hypothesis 4. The addition of menopausal hormone therapy using combined oestrogen with progestogen did not improve arterial relaxation in postmenopausal women with established coronary heart disease. / Hypothesis 2. This hypothesis examined three different types of commonly used menopausal HT. That unopposed oestrogen (2a), oestrogen combined with a progestogen (2b and 2d) or a synthetic steriod that has oestrogenic, progestogenic as well as androgenic activity (tibolone, 2c), reverse the reduction in arterial relaxation following menopause in Hong Kong Chinese women. / Hypothesis 3. That menopausal hormone therapy using oestrogen combined with progestogen given in either continuous (3a) or cyclical (3b) regimens improves arterial relaxation in postmenopausal Hong Kong Chinese women. / Hypothesis 4. That menopausal hormone therapy using combined oestrogen with progestogen improves arterial relaxation in postmenopausal Hong Kong Chinese women with established coronary heart disease. / Menopausal HT can in general at least partially reverse changes in arterial relaxation in postmenopausal women. Different types of menopausal HT exhibit different effects on arterial relaxation. In healthy vessels, menopause HT mainly reverses the endothelium-dependent vascular effect, but it remains unclear how menopausal HT affects the endothelium-independent vascular effect. However, with established coronary heart disease, menopausal HT cannot reverse the changes in vascular reactivity. / Summary. Menopause results in a reduction in arterial relaxation. However, GnRHa temporarily induced menopause in young women, the endothelium-independent vasodilatation was not impaired. This difference can be partly explained by the difference in age as vascular reactivity is age dependent. Secondly, GnRHa works with an initial phase of increase in oestrogen production resulting in a shorter duration of hypo-oestrogenism resulting in the lack of impairment on endothelium-independent vasodilatation. / This thesis tested the following hypotheses: Hypothesis 1. That vascular reactivity decreases after the menopause as shown in premenopausal Hong Kong Chinese women with either a surgical (1a) or a medically induced (1b) menopause. / This thesis will examine the effects of menopause and menopausal HT on arterial reactivity which is an indirect measurement of vascular function. Previous studies have shown that oestrogen is a potent coronary artery vasodilator, and this effect may be mediated via both endothelium-dependent and endothelium-independent mechanisms. One method of assessing vascular reactivity is to use ultrasound measurement of changes in brachial artery diameter in response to certain stimuli. Using this technique, changes in both endothelium-dependent and endothelium-independent vasodilatation can be measured. Increased rather than decreased arterial relaxation after stimulus can be viewed as a favourable response. / Yim, So-fan. / Adviser: C. J. Haines. / Source: Dissertation Abstracts International, Volume: 68-09, Section: B, page: 5873. / Thesis (M.D.)--Chinese University of Hong Kong, 2006. / Includes bibliographical references (p. 159-194). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / School code: 1307.

Cardiovascular disease remains the leading cause of death worldwide. A lack of curative treatments and a shortage of transplant hearts necessitate new approaches to cardiac repair. Recent advances, including the advent of pluripotent stem cell-derived cardiomyocytes and the development of tissue engineering techniques, represent promising new directions to remuscularize the heart or induce endogenous regeneration. However, these approaches are currently limited by the immaturity of differentiated cardiomyocytes and the inability of cardiomyocytes to functionally integrate with the damaged myocardium. Mimicking the cardiomyocyte niche, the myriad signals surrounding the cardiomyocyte, may enhance the utility of these cells. In this dissertation, each of the three aspects of the cardiomyocyte niche: physical signals, the extracellular matrix, and soluble factors, are examined for their ability to guide cardiomyocyte growth and function. We first explore the effect of electrical stimulation, a physical signal pervasive in the heart, on pluripotent stem cell-derived cardiomyocyte development and function. Stimulated cardiomyocytes are more mature, show greater cell-cell connectivity, and are more resistant to tachycardic stress. Cardiomyocytes adapt their beating rate to the stimulation frequency, an effect mediated by the emergence of a rapidly depolarizing cell type and ion channel expression. We next engineer cardiovascular tissue architecture, critical components of the extracellular matrix, using a micromolding approach and determine geometric parameters necessary for the induction of cardiomyocyte alignment and tissue synchrony. We finally test pluripotent stem cell-derived cardiomyocyte exosomes, soluble nanovesicles specifically packaged and secreted by the cell, in vitro and in vivo, demonstrating functional improvement and reduction of arrhythmia in the heart. Therefore, the use of the cardiomyocyte niche supports the interrogation of cellular function to enable new cell-based approaches for the reduction of arrhythmia or induction of repair in the heart.

University of Macau / Institute of Chinese Medical Sciences

No description available.

Imaging guidance may allow minimally invasive alternatives to open surgical exposure and help reduce procedure risk and morbidity. The inherent vascular and soft-tissue contrast of MRI make it an appealing imaging modality to guide cardiovascular interventional procedures. Advances in real-time MRI have made MRI-guided procedures a realistic possibility. The MR environment, however, introduces additional challenges to the development of compatible, conspicuous and safe devices. The overall goal of this work was to enable selected MRI-guided cardiovascular interventional procedures with clearly visible MR devices. In the first part of this work, we developed actively visualized devices for three distinct MRI-guided interventional procedures and techniques to assess their signal performance. We then investigated factors influencing complex device safety in the MR environment and evaluated a technique to better determine and monitor potential device heating. This input contributed to the development of a system to further improve device safety with continual device monitoring and dynamic scanner feedback control. In the final part of this work, we demonstrated the utility of MRI guidance and actively visualized devices to enable traditional and complex cardiovascular access. Together these provide important elements to bring MRI-guided cardiovascular interventional procedures closer to clinical implementation.

University of Macau / Institute of Chinese Medical Sciences

M. Tech (Department of Biotechnology, Faculty of Applied and Computer Sciences) Vaal University of Technology. / Background: Cardiovascular diseases are one of the most common causes of death worldwide. This is not only a problem in developed countries, it is of major concern for public health in developing countries as well. Increased homocysteine is an independent risk factor for cardiovascular diseases. Nutritional deficiencies of folate, vitamin B6 and vitamin B12 are associated with hyperhomocysteinemia. MTHFR A1298C, a single nucleotide polymorphism, is similarly linked with higher concentrations of homocysteine. The aim of this study was to determine the prevalence of MTHFR A1298C in a black elderly population, along with folate, vitamin B6 and vitamin B12 and to evaluate the effect on homocysteine levels. Methodology: The research design was an observational cross-sectional study and was ethically approved. A total of 84 elderly who attend a day-care centre (also met inclusion criteria) were purposively selected. DNA was extracted and frozen on the day of blood collection. The MTHFR A1298C genotype was determined with real time PCR. Homocysteine, folate, vitamin B6 and vitamin B12 serum levels were detected with commercial assay kits. Results: Homocysteine was found to be elevated with a median of 17.78 µmol/L (interquartile range 13.98-21.03 µmol/L). Serum folate, vitamin B6 and vitamin B12 medians were in the normal range. Although, 5.95% and 22.62% of the population were deficient and possibly deficient for vitamin B12, respectively. MTHFR A1298C frequency was as follow: 89.29% (AA), 9.52% (AC) and 1.19% (CC), with no significant correlation (p>0.05) with homocysteine. Vitamin B12 correlated significantly with homocysteine levels. Conclusion: Vitamin B12 deficiency had an effect on homocysteine levels. Overall, nutritional deficiencies are not responsible for the hyperhomocysteinemia in this population. In conclusion from this study showed MTHFR A1298C frequency in black South Africans does not contribute to homocysteine as a risk factor for cardiovascular disease. Keywords: Cardiovascular disease, elderly, folate, homocysteine, MTHFR A1298C, vitamin B6, vitamin B12.

Cardiovascular disease is the leading cause of death in the United States and the world. Progress in the development of new therapeutic strategies is hindered by shortcomings in our understanding of human myocardial pathophysiology and limitations in the ability of preclinical models to accurately predict successful clinical translation. The development of engineered models of the myocardium comprised of human cells derived from induced pluripotent stem cells has emerged as a promising strategy to overcome these problems. This dissertation builds on this work by developing a new engineered cardiac tissue platform and then utilizing it to investigate three distinct myocardial pathologies: (1) genetic restrictive cardiomyopathy, (2) autoimmune mediated myocardial injury, and (3) myocardial ischemia and reperfusion injury. Results from these studies provide new insights into therapeutic strategies for the first two conditions and describe substantial progress towards the creation of an innovative model of the third.

Appendum consists of last two leaves. / Copies of author's previously published articles inserted. / Bibliography: leaves 241-283. / xviii, 284 leaves : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / The studies described were designed to identify and address (through the application of relatively novel and potentially useful adjunctive therapeutic strategies) some of the determinants of sub-optimal therapeutic response in intermediate coronary syndrome and chronic congestive heart failure; especially when targeted towards those patients who fail to gain the maximal benefit from pre-existing modalities of pharmacological treatment. / Thesis (Ph.D.)--University of Adelaide, Dept. of Medicine, 1999