Problem: The risk of serious postoperative cardiovascular and respiratory complications (SPCRCs) in patients with obstructive sleep apnea (OSA) is poorly defined. Methods: In this cohort study (n = 21221), patients with clinically diagnosed OSA were matched to controls without OSA to compare the risk of postoperative death and SPCRCs in an administrative database. Results: Compared to non-OSA controls, OSA patients were at increased risk of postoperative respiratory failure both before and after diagnosis with OSA. Prior to diagnosis, OSA patients, particularly those with severe OSA, were also at increased risk of cardiac arrest and SPCRCs . After diagnosis with OSA, except for postoperative respiratory failure, the risk of SPCRC’s was not different from controls. Also, the risk of postoperative death among OSA patients after diagnosis was not different from controls. Other important predictors of SPCRCs and death included admission in an intensive care unit at the time of surgery, a history of congestive heart failure, a higher Charlson comorbidity index score and the type of surgery. Conclusions: OSA was associated with an increased risk of SPCRCs, especially prior to diagnosis and in severe disease. This suggests that screening for and treating OSA in preoperative patients would reduce the risk of SPCRCs. However, the significant influences of the type of surgery and the presence of medical comorbidities on the risks of SPCRCs and death, regardless of the presence of OSA, must be considered in planning efficient and equitable interventions to reduce these risks.

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In vertebrates, the heart is the first organ to form and function. The basic steps and molecular pathways involved in heart development are highly conserved. Myocardial progenitor-fated cells are among the first cells to migrate during gastrulation away from the primitive streak. These cells move bilaterally to populate the heart-forming region (HFR) in the anterior lateral plate mesoderm (ALPM). Once cells have reached the HFR, they receive the signals necessary to differentiate into myocardial progenitor cells. It is clear that the development of myocardial progenitor cells entails the migration of cells from the lateral embryonic margin to the ALPM. However, it is unclear whether cells are specified for a myocardial progenitor fate early in embryogenesis, a step that may promote their migration specifically to the ALPM, or whether the migration of cells to the ALPM alone is sufficient for differentiation into myocardial progenitor cells. A zebrafish mutant, grinch (grn), was indentified in which there is a defect in the development of myocardial progenitor cells. The mutation resulting in the grn phenotype was mapped to the gene encoding the G protein-coupled receptor Apelin receptor b (Aplnrb). I have used the aplnrb mutant embryo, as well as morpholino-mediated knockdown (morphant embryos) of aplnrb, and its paralog aplnra, to determine the function of Aplnr signaling in myocardial progenitor development. Results demonstrate that Aplnr signaling is necessary for the migration of cells from the lateral embryonic margin of the zebrafish embryo to the heart-forming region. Interestingly, this entails a novel cell-non-autonomous function for Aplnr signaling. Furthermore, both the only identified ligand for the receptor, Apelin, and the canonical mediators of Aplnr signaling, Gαi/o proteins, appear to be dispensable for this process. Loss of Aplnr signaling also appears to affect embryonic patterning of the early embryo through subtle perturbations of Nodal, Wnt, and Bmp signaling and attenuation of Nodal signaling can partially recapitulate the aplnr morphant cardiac phenotype. Taken together, my results suggest that Aplnr signaling plays a role in creating an environment that allows for the migration of cells to the heart-forming region, possibly through the regulation of early embryonic patterning.

In vertebrates, the heart is the first organ to form and function. The basic steps and molecular pathways involved in heart development are highly conserved. Myocardial progenitor-fated cells are among the first cells to migrate during gastrulation away from the primitive streak. These cells move bilaterally to populate the heart-forming region (HFR) in the anterior lateral plate mesoderm (ALPM). Once cells have reached the HFR, they receive the signals necessary to differentiate into myocardial progenitor cells. It is clear that the development of myocardial progenitor cells entails the migration of cells from the lateral embryonic margin to the ALPM. However, it is unclear whether cells are specified for a myocardial progenitor fate early in embryogenesis, a step that may promote their migration specifically to the ALPM, or whether the migration of cells to the ALPM alone is sufficient for differentiation into myocardial progenitor cells. A zebrafish mutant, grinch (grn), was indentified in which there is a defect in the development of myocardial progenitor cells. The mutation resulting in the grn phenotype was mapped to the gene encoding the G protein-coupled receptor Apelin receptor b (Aplnrb). I have used the aplnrb mutant embryo, as well as morpholino-mediated knockdown (morphant embryos) of aplnrb, and its paralog aplnra, to determine the function of Aplnr signaling in myocardial progenitor development. Results demonstrate that Aplnr signaling is necessary for the migration of cells from the lateral embryonic margin of the zebrafish embryo to the heart-forming region. Interestingly, this entails a novel cell-non-autonomous function for Aplnr signaling. Furthermore, both the only identified ligand for the receptor, Apelin, and the canonical mediators of Aplnr signaling, Gαi/o proteins, appear to be dispensable for this process. Loss of Aplnr signaling also appears to affect embryonic patterning of the early embryo through subtle perturbations of Nodal, Wnt, and Bmp signaling and attenuation of Nodal signaling can partially recapitulate the aplnr morphant cardiac phenotype. Taken together, my results suggest that Aplnr signaling plays a role in creating an environment that allows for the migration of cells to the heart-forming region, possibly through the regulation of early embryonic patterning.

Phosphatidylcholine (PC) is made in all nucleated mammalian cells via the CDP-choline pathway. Another major pathway for PC biosynthesis in liver is catalyzed by phosphatidylethanolamine N-methyltransferase (PEMT). We have identified 3T3-L1 adipocytes as a cell culture model that expresses PEMT endogenously. Analysis of the proximal PEMT promoter in 3T3-L1 adipocytes revealed an important regulatory region. Sp1 binds to a GC-rich site within this section of the promoter and inhibits PEMT transcriptional activity. Tamoxifen is an anti-estrogen drug widely used for the treatment of hormone-responsive breast cancer but has a frequent side-effect of increasing accumulation of lipid in the liver (hepatic steatosis). Tamoxifen represses PEMT gene expression by promoting Sp1 binding to the promoter. However, decreased catalytic activity of PEMT was not a major initial contributor to tamoxifen-mediated hepatic steatosis. We found that increased de novo fatty acid synthesis is the primary event which leads to tamoxifen-induced steatosis in mouse liver. Tamoxifen did not significantly alter hepatic fatty acid uptake, triacylglycerol secretion or fatty acid oxidation. Finally, we provide evidence that deletion of the PEMT gene in a well-established mouse model of atherosclerosis (apolipoprotein E deficient) reduces the formation of aortic lesions and prevents the associated development of dilated cardiomyopathy. This beneficial effect is likely due a reduction of atherogenic lipoproteins. These results indicate that treatment strategies aimed at the inhibition of PEMT could prevent the development of atherosclerosis that predisposes individuals to heart failure.

Myocardial infarction is the most common cause of heart failure and remains one of the leading causes of morbidity and mortality in humans. Stem cells are important in the maintenance and repair of adult tissues. Hoechst effluxing cells, termed side population cells are a rare subset of cells found in adult tissues that are highly enriched for stem and progenitor cell activity. Recent studies have suggested that Sca-1+/CD31- cardiac side population cells are capable of differentiation into cardiomyocytes in vitro. However, the response of cardiac side population cells to myocardial injury remains unknown in vivo. In this study, we directly transplanted Sca-1+/CD31- cardiac side population cells into an acutely infarcted mouse heart. After two weeks, the transplanted cells were found to express cardiomyocyte or endothelial cell markers. Importantly, when these cells were transplanted into a remote nonischemic part of the heart after MI, they were able to migrate to the damaged myocardium. Consistent with these cells homing property, we found that SDF-1α, a chemotactic chemokine and its receptor, CXCR4 were up-regulated in the damaged myocardium and on Sca-1+/CD31- cardiac SP cells respectively following an acute myocardial infarction. We further showed that SDF-1α was able to induce migration of Sca-1+/CD31- cardiac side population cells in vitro. Our results have therefore suggested that Sca-1+/CD31- cardiac side population cells are able to migrate to damaged myocardium from non-ischemic myocardium and differentiate into cardiomyocytes as well as endothelial cells in the acutely infarcted mouse heart. We postulate that the SDF-1α/CXCR4 interaction may play an important role in the migration of these cells. Understanding and enhancing these processes may hold enormous potential possibilities for therapeutic myocardial regeneration for the treatment of cardiovascular disease.

Thesis (M.S.)--West Virginia University, 2008. / Title from document title page. Document formatted into pages; contains vi, 79 p. Includes abstract. Includes bibliographical references.

Thesis (Ph. D.)--University of Hong Kong, 2007. / Also available in print.

Diss. (sammanfattning) Uppsala : Univ., 2001. / Härtill 5 uppsatser.

Thesis (Ph. D.)--University of Hong Kong, 2007. / Also available online.