Date of Award

2014

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Pharmacology

First Advisor

Robert J. Levy

Second Advisor

Harry Ischiropoulos

Abstract

ABSTRACT

Abigail J. Christian

Robert J. Levy

Harry Ischiropoulos

Bioprosthetic heart valves (BHV) are widely used in interventions for symptomatic valvular disease; however, they begin to fail clinically after 10 years, most frequently due to structural deterioration. Calcification has been considered the major mechanism of BHV degeneration although other mechanisms may be involved. In this work, we investigated the hypothesis that oxidants contribute to BHV structural degeneration. BHV have been shown to elicit an inflammatory response from the patient, thereby resulting in the production of reactive oxygen and reactive nitrogen species which may degrade BHV. To determine the role of oxidants in BHV degeneration, we analyzed clinically failed BHV explants for markers of oxidation and utilized experimental systems to identify the consequences of BHV oxidation. Clinical BHV explants were found to have elevated levels of the tyrosine oxidation product dityrosine, therefore indicating that BHV are susceptible to oxidation. Exposure of the BHV material glutaraldehyde-fixed bovine pericardium (BP) to oxidizing conditions demonstrated that oxidation of BHV results in the loss of glutaraldehyde cross-links, disruption of the collagen structure, and an increase in susceptibility to proteolytic degradation. To address this mechanism of BHV structural degeneration, we developed two antioxidant delivery strategies. Our first approach involved covalent immobilization of the oxidant scavenger 3-(4-hydroxy-3,5-di-tert-butylphenyl) propyl amine (DBP) to BHV leaflet materials whereas the second method utilized passive incorporation of a catalytic antioxidant, a superoxide dismutase (SOD) mimetic, into the material. Both strategies demonstrated efficient delivery of an antioxidant to the BHV material. DBP mitigated structural degradation of BP induced by exposure to oxidizing conditions and provided resistance to calcification in the rat subdermal implant model. The SOD mimetic approach demonstrated SOD activity following incorporation into BP as well as after 90 day implantation in either the rat subdermal implant model or sheep circulatory patch model; thereby supporting the hypothesis that SOD mimetics may provide sustained protection from oxidants. These studies demonstrate that oxidants contribute to the structural degeneration of BHV and that an antioxidant material modification may be used to mitigate this process and to potentially improve the durability of BHV.

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