Kok Dick Shun , Louis. / Thesis (Ph.D.)--Chinese University of Honbg Kong, 1997. / Includes bibliographical references (p. i-xiii). / 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 Company, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web.

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Cardiac disease is the leading cause of death in the United States, despite the continuing efforts contributed to scientific research and disease management in the past few decades. However many advances have been made in cardiovascular research in recent decades and one of the advances is the development of human induced pluripotent stem cell(iPSC)-based disease models. The human iPSC-based disease models are derived from the somatic cells of patients with cardiac diseases and capture the genotypes of the original patients, which make them more ideal for mimicking human diseases compared with conventional rodent models. So far, the iPSC-based disease models have been used to model several types of cardiac diseases, one of which is the focus of this work-Timothy syndrome. Timothy syndrome is caused by the missense mutations in the CACNA1C gene encoding the voltage-gated calcium channel CaV1.2, which plays an essential role in cardiac function. The disease is a multisystem disorder that is featured by long QT syndrome and syndactyly. Timothy syndrome patients are treated clinically with beta-adrenergic blockers, calcium channel blockers, and sodium channel blockers. However, these regimens are insufficient to prevent lethal arrhythmias in Timothy syndrome patients, especially infants with Timothy syndrome. Therefore, new therapeutics to prevent the lethal arrhythmias in Timothy syndrome patients are needed until the age when an implantable defibrillator is available. The iPSC-based model of Timothy syndrome was first reported in 2011. The previous report showed that the Timothy syndrome iPSC-derived cardiomyocytes demonstrated several cellular phenotypes including abnormal contractions, abnormal electrophysiological properties and abnormal calcium handling, which were consistent with the clinical features of the patients that the iPSCs were derived from. In addition, the authors demonstrated that Roscovitine, a cyclin-dependent kinase (CDK) inhibitor, could rescue the cellular phenotypes in Timothy syndrome cardiomyocytes. However, the mechanisms underlying the beneficial effects of Roscovitine on Timothy syndrome cardiomyocytes were not fully elucidated. This work will employ the iPSC-based model of Timothy syndrome to investigate the mechanisms underlying the beneficial effects of Roscovitine on Timothy syndrome cardiomyocytes and search for additional therapeutic compounds and targets for Timothy syndrome. In chapter 1 of this work, we presented new methods to generate iPSCs from human skin fibroblasts or hair keratinocytes, and to differentiate iPSCs into cardiomyocytes in a monolayer format. The major advantage of the two new methods is that they are technically simple and generally applicable for samples from healthy control donors and patients with cardiac diseases. The new methods enabled us to generate a sufficient amount of Timothy syndrome cardiomyocytes from iPSCs derived from the skin fibroblasts of Timothy syndrome patients, which became the foundation for the subsequent mechanistic study. Chapter 2 presents the identification of CDK5 as a new therapeutic target for Timothy syndrome. As introduced above, the previous report demonstrated that Roscovitine, a CDK inhibitor, could rescue the cellular phenotypes in Timothy syndrome cardiomyocytes. However, the mechanisms underlying the beneficial effects of Roscovitine on Timothy syndrome cardiomyocytes were not fully elucidated. To identify additional therapeutic compounds for Timothy syndrome and investigate the mechanisms underlying the therapeutic effects of Roscovitine on Timothy syndrome cardiomyocytes, we conducted a phenotypic screen using Timothy syndrome cardiomyocytes to screen through twenty Roscovitine analogs and four CDK inhibitors with different specificities for different CDKs. Four positive compounds were identified from the screen. When we summarized the CDK targets of the four positive compounds and the lead compound Roscovitine, it was found that four out of the five positive compounds shared a common CDK target, which is CDK5, indicating that CDK5 could be involved in the pathogenesis of Timothy syndrome as a therapeutic target. We next validated CDK5 as a new therapeutic target for Timothy syndrome using two independent approaches. The two approaches are expressing a dominant negative mutant of CDK5 and expressing short hairpin RNAs targeting CDK5 in Timothy syndrome cardiomyocytes using lentiviruses. Both approaches led to CDK5 inhibition in Timothy syndrome cardiomyocytes and we examined the changes in the cellular phenotypes in Timothy syndrome cardiomyocytes with CDK5 inhibition. The results indicated that CDK5 inhibition alleviated all the previously-reported phenotypes in Timothy syndrome cardiomyocytes. To investigate the mechanisms underlying the beneficial effects of CDK5 inhibition on Timothy syndrome cardiomyocytes, we examined the expression of CDK5 activator p35 and the activity of CDK5 in Timothy syndrome cardiomyocytes. We found that Timothy syndrome cardiomyocytes showed a higher expression of CDK5 activator p35 and a higher activity of CDK5 compared with control cardiomyocytes. When we over-expressed CDK5 in control cardiomyocytes, we found that CDK5 over-expression caused a change in the function of CaV1.2 channels in control cardiomyocytes that resembled the phenotype in Timothy syndrome cardiomyocytes. In summary of the results, we propose that in Timothy syndrome cardiomyocytes, the increased expression of CDK5 activator p35 causes CDK5 hyper-activation, which enhances the abnormal function of the mutant CaV1.2 channels, leading to more severe phenotypes. Thus, CDK5 inhibition alleviates the phenotypes in Timothy syndrome cardiomyocytes. The results in this chapter reveal that CDK5 is a new therapeutic target for Timothy syndrome and CDK5-specific inhibitors can potentially be developed into new therapeutics for Timothy syndrome. However, we found that the currently-available chemical inhibitors for CDK5 are not highly-selective and have several significant side effects that make them not ideal candidates to be developed into new therapeutics for cardiac diseases. Therefore new therapeutic compounds and targets are still needed for Timothy syndrome. Chapter 3 presents the identification of the sigma-1 receptor as a new therapeutic target for Timothy syndrome. Due to the side effects associated with the currently-available chemical inhibitors for CDK5, we made an effort to search for an additional therapeutic target and therapeutic compounds for Timothy syndrome. We reasoned that instead of directly inhibiting CDK5, we could potentially alleviate the phenotypes in Timothy syndrome cardiomyocytes by affecting the CDK5 activator p35 and this idea led us to the sigma-1 receptor. After we looked into the sigma-1 receptor, we found that in addition to being reported to modulate p35 protein level, the sigma-1 receptor had also been reported to modulate calcium homeostasis, which is another favorable effect for Timothy syndrome cardiomyocytes. Therefore we hypothesized that the activation of the sigma-1 receptor could be beneficial for Timothy syndrome cardiomyocytes, which feature an increased expression of p35 and a dysregulation of calcium homeostasis. To test this hypothesis, we examined the effects of two sigma-1 receptor agonists, one of which is a FDA-approved drug, on the phenotypes in Timothy syndrome cardiomyocytes. The results demonstrated that the treatment of the two sigma-1 receptor agonists alleviated the previously-reported phenotypes in Timothy syndrome cardiomyocytes. We also examined the effects of the two sigma-1 receptor agonists on the functions of control cardiomyocytes and found that the treatment of the two sigma-1 receptor agonists did not have significant side effects on the regular contractions and normal calcium transients in control cardiomyocytes. Overall, the results reveal that the sigma-1 receptor is a new therapeutic target for Timothy syndrome. The results also demonstrate that the two sigma-1 receptor agonists that we tested are promising lead compounds that can developed into novel therapeutics for Timothy syndrome in the future. Since one of the sigma-1 receptor agonists that we tested is a FDA-approved drug, this drug could potentially be used directly in Timothy syndrome patients for treating the cardiac arrhythmias in the near future. In summary, this work is a proof of concept that the iPSC-based models of cardiac diseases can be used to generate novel insights into disease pathogenesis, and to identify new therapeutic targets and compounds for cardiac diseases, and in particular for Timothy syndrome. The therapeutic targets and compounds that we have identified in this work would be helpful for the development of novel therapeutics for treating the lethal arrhythmias in Timothy syndrome patients in the future.

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Diabetes Mellitus (DM) and insulin resistant (IR) are highly prevalent among heart failure (HF) patients. There is now increasing evidence to suggest a bidirectional relationship between IR and HF. DM and IR not only lead to heart failure, but heart failure can also lead to the development of DM or IR. The degree of IR also correlates with the severity and mortality of CHF. The pathophysiology of IR in CHF has yet to be fully defined. Activation of sympathetic nervous system, abnormal regulation of adipocytokines systems, activation of inflammatory and coagulation cascade, accumulation of glycated products, endothelial dysfunction and hyperinsulinaemia are potential explanations of the development of IR in CHF. Additionally, it remains to be determined if IR is merely a marker reflecting the severity of CHF or whether it contributes to the disease in CHF. If IR is truly a culprit that worsens CHF, reversing IR may potentially be a new target for treatment in CHF, which may result in an improvement in symptoms and even mortality in patients with CHF. However, there are concerns over the use of certain insulin sensitizers, most notably, the thiazolidinediones (TZDs), which has been linked with increased risk of hospitalizations for CHF and concerns regarding its association with increased myocardial infarction. Despite previous concerns of lactic acidosis, there is now evidence that metformin may not only be safe but could potentially be useful in the setting of CHF. We have conducted a randomised double-blind, placebo-controlled trial testing the hypothesis of reversing IR with metformin in insulin-resistant CHF will have beneficial effects. If IR is a possible target for the treatment of CHF, what are the new and potential treatment modalities? We have now had better understandings of the adipocytokines systems, which may prove to be a therapeutic option to improve IR in CHF. AMP-activated protein kinase (AMPK) pathway has become the focus of research as a novel therapeutic target in cardio-metabolic disease. It has been shown to mediate, at least in part, the effects of a number of physiological and pharmacological factors that improve IR. It also exerts beneficial effects on the vasculature and the heart. There have been some new AMPK activators that are currently being tested in vivo setting or phase 1-2 trials, and the early results are somewhat promising. Increased understandings and refreshed insights of IR and CHF have opened a new horizon and encouraged us to explore more therapeutics options in CHF.

Approximately 25% of those hospitalized with congestive heart failure are readmitted within 30 days after discharge. Because researchers and policy makers consider hospital readmission within 30 days for patients with heart failure to be a quality of care issue, the Centers for Medicare and Medicaid Services has imposed financial penalties of up to 3% of a hospital's Medicare revenue for 1 year for excessive readmissions, potentially impacting the financial sustainability of some organizations. The purpose of the study was to address the research gap regarding the outcome quality measure of hospital admissions from the emergency department (ED) and 2 each process and structure variables. The Donabedian conceptual framework was used to assess quality of care through the triad of structure, process, and outcome. The quantitative study comprised analysis of cross-sectional archival data from the 2015 National Hospital Ambulatory Care Survey using cross-tabulations with chi-square followed by multiple logistic regression analysis. Findings showed that process quality measures of being seen in the ED within 72 hours and total laboratory tests obtained in the ED were predictive of lower likelihood of admission. The structure quality measure of insurance was not predictive; however, being seen by provider type consulting physician was predictive of higher likelihood of admission, whereas being seen by a nurse practitioner was predictive of lower likelihood of hospital admission. The implications of this study for social change are helping hospitals maintain financial stability through avoidance of financial penalties for heart failure readmission, supporting access to care for patients by avoiding hospital closures.

Heart failure (HF) has a global significance for the older population and is the most common reason for hospitalization. Patients with HF can reduce their risk for hospital readmissions and adverse outcomes through self-management of their disease. Nurses are responsible for educating patients about HF self-management; however, nurses at the project site lacked sufficient understanding and confidence to perform adequate HF patient education, creating a gap in practice. This project was guided by Pender's health promotion model and adult learning theory with the goal to increase nurses' knowledge and confidence with the self-management principles of HF. The purpose of this project was to develop an educational program for nurses to increase their knowledge of HF disease management and patient self-management principles. The education program was supported by research literature and recommendations from the Agency for Healthcare Research and Quality, in addition to input from a planning team consisting of 3 nursing leaders from the project site. The planning team provided process evaluation regarding satisfaction with the planning process by completing an anonymous, 10-question, Likert-type survey. Seven project evaluations were completed and all respondents indicated that they agreed or strongly agreed in response to questions regarding the effectiveness of the project, it's planning, and the leader. At the completion of the project, the education program was delivered to the project site, with a plan for later implementation and learner evaluation using assessment tools of HF knowledge and confidence. This project has the potential to achieve positive social change in relation to nurses' commitment to improving patient outcomes through quality initiatives and dedication to the implementation of evidence-based practice, thus, promoting positive patient outcomes.

Heart failure (HF) is an escalating chronic disorder that impacts patients, families, and society. HF necessitates efficient transition of care and complex self-care knowledge in a population often burdened with low health literacy and high readmission rates. The purpose of this project was to improve transition of discharged HF patients from a Level 1 trauma system in a mostly rural area of South Carolina to its affiliated nurse-led HF clinic. The no-show rate for initial visits to the health care system's outpatient HF clinic by postdischarge patients was 59%. Using Henderson's need theory and Stevens's knowledge transformation model for theoretical guidance, a quality improvement project was conducted to identify factors related to no-show behavior in initial HF clinic visits using a retrospective chart audit of the first 50 no-show patients in a 90-day period. Data were collected from the electronic medical record and analyzed through descriptive statistics. Frequently noted factors were lack of literacy screening, use of assistive devices, and access issues related to distance to travel and transportation to the HF clinic. Recommendations included mandatory literacy level screening on admission, integration of an evidence-based health literacy screening tool into the electronic record, use of satellite HF clinic services, and consideration of a mobile HF clinic on wheels to better serve the rural population. Social change is expected to occur in this vulnerable population through these efforts to address health literacy issues and increase access to clinic care after hospital discharge.

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Mutations in BBS6 cause two clinically distinct syndromes, Bardet-Biedl syndrome (BBS), a syndrome caused by defects in cilia transport and function, as well as McKusick-Kaufman syndrome, a genetic disorder characterized by congenital heart defects. Congenital heart defects are rare in BBS, and McKusick-Kaufman syndrome patients do not develop retinitis pigmentosa. Therefore, the McKusick-Kaufman syndrome allele may highlight cellular functions of BBS6 distinct from the presently understood functions in the cilia. In support, we find that the McKusick-Kaufman syndrome disease-associated allele, BBS6H84Y; A242S, maintains cilia function. We demonstrate that BBS6 is actively transported between the cytoplasm and nucleus, and that BBS6H84Y; A242S, is defective in this transport. We developed a transgenic zebrafish with inducible bbs6 to identify novel binding partners of BBS6, and we find interaction with the SWI/SNF chromatin remodeling protein Smarcc1a (SMARCC1 in humans). We demonstrate that through this interaction, BBS6 modulates the sub-cellular localization of SMARCC1 and find, by transcriptional profiling, similar transcriptional changes following smarcc1a and bbs6 manipulation. Our work identifies a new function for BBS6 in nuclear-cytoplasmic transport, and provides insight into the disease mechanism underlying the congenital heart defects in McKusick-Kaufman syndrome patients.