No description available.

No description available.

Tricuspid regurgitation (TR), back flow of blood from the right ventricle to the right atrium, has been reported in approximately 85% of the population, with 16% having mild or severe TR. Patients with untreated moderate to severe TR are likely to experience decreased exercise capacity and have increased morbidity and mortality, thus affecting the patient's quality of life. Current methods of repair offer limited rates of success, and many patients require further operations to correct returning levels of TR. Incomplete repair may be due to incomplete understanding of the functional anatomy and mechanics of the TV and the underlying causes of TR. It was hypothesized that alterations in the geometry of tricuspid valve annular and subvalvular apparatus induced by ventricular dilatation determine the severity of TR. In vivo measurements of papillary muscle (PM) position in patients with single or biventricular dilatation revealed PM displacement away from the center of the annulus as compared to control patients. Additionally, pulmonary arterial pressure, annulus area, ventricular size and apical displacement of the anterior PM were highly correlated with the severity of TR. An in vitro right-heart simulator was developed to investigate isolated mechanics of TR. Through these in vitro studies it was demonstrated that the tricuspid valve begins to leak at only 40% dilation, much lower than the mitral valve. Additionally, it was shown that isolated PM displacement resulted in significant TR. The highest levels of TR were achieved with a combination of annular dilatation and PM displacement. Alterations in leaflet coaptation, as quantified by measuring the amount of leaflet available for coaptation and leaflet mobility were observed with annular dilatation and PM displacement, both isolated and combined. The changes in leaflet coaptation resulted in redistribution of the forces on the chords originating from the anterior PM and inserting into the anterior and posterior leaflets. The findings herein provide the clinical and scientific community with a mechanistic understanding of the tricuspid valve to further improve intervention and repair of TV disease.

[Truncated abstract] The enlargement of the heart, also known as myocardial hypertrophy, is thought to be a compensatory process that maintains the mechanical function of the heart in response to stress factors such as pressure or volume overload. Although this process is initially compensatory, it frequently results in heart failure and death. Cardiac hypertrophy is a complex process involving changes in the individual cardiac muscle cells, cardiac myocytes. As well as the morphological changes that result from hypertrophy, there are molecular changes within each cell that regulate the hypertrophic process. These molecular changes involve many different pathways within the cardiac myocytes and remain poorly understood . . . Both STAT3α and β overexpression resulted in the upregulation of the VEGF, MnSOD and SOCS-3 genes. This indicates that in the heart, STAT3β is able to activate the gene expression of these genes in a similar manner to STAT3α. However, STAT3α or β activation alone is not enough to induce cardiac hypertrophy. In conclusion, the results presented in this thesis determined a novel role for ERK in the induction of cell death in the heart and revealed many changes in cardiac gene expression following ERK activation. These genes may be the mediators of ERK responses and their identification provides valuable information and direction for further research in this area. One consequence of ERK activation was the negative regulation of the STAT3 pathway. Further investigation revealed for the first time that the STAT3 proteins themselves may not be involved in the induction of cardiac hypertrophy and that STAT3β, initially thought to be a transcriptional repressor, can induce the expression of genes that are known to be activated by STAT3α in the heart. Therefore, these results help to better understand the roles of these two signalling pathways in the heart.