Remodeling of the extracellular matrix components of the mitral valve due to alterations in the mechanical and chemical environments of the tissue
Barzilla, Janet Christine Elliott
Grande-Allen, K. Jane
Doctor of Philosophy
This body of research explored mitral valve remodeling due to changes in the mechanical and chemical environments of the tissue in order to better predict patient response to medical device and drug therapies. This work was novel both in its characterization of the mitral valve and in the consideration of the impacts of the biological environment on the multilayered valve structure. Left ventricular dilation due to congestive heart failure (CHF) changes the mechanical forces experienced by the mitral valve. Collagen, cellular, glycosaminoglycan, and proteoglycan compositions of valve tissues were therefore compared between CHF patients treated with and without the left ventricular assist device (LVAD). Mechanical properties of these tissues were also tested to assess effects of matrix changes on valve function. Since mechanical stimulation was determined to be required to maintain valve structure and function, a novel splashing bioreactor was then designed to maintain the valve mechanical environment in vitro in preparation for studies altering the chemical environment of the tissue. Alter validation, this bioreactor was used to study initial changes to valve structure alter two weeks of organ culture with media containing the serotonin receptor agonists serotonin and norfenfluramine (fen-phen) as well as a receptor antagonist. In the mechanical stimulation study, CHF valve tissue exhibited fibrotic remodeling compared to normal tissue, impeding normal mitral valve function. LVAD treatment, while it tended to restore functionality of the mitral valve chordae, encouraged compensatory remodeling that did not improve leaflet structure or mechanical behavior. Conversely, the gentle stretching provided by bioreactor was deemed sufficient to maintain matrix composition after two weeks of culture. Serotonin and norfenfluramine exposure appeared to upregulate different proteoglycans within the mitral valve structure, and exposure to a serotonin receptor antagonist had varying levels in success in blocking these drug effects. The results from these studies showed that changes to the mechanical (CHF and LVAD) and chemical (serotonin and norfenfluramine) environments altered mitral valve tissue structure and function. These effects of device use and drug therapies should be considered when assessing treatment for pathologies, such as CHF and obesity, which may not appear to directly impact the mitral valve.