ELASTIN DAMAGE: MECHANISM OF BIOPROSTHETIC VALUE FAILURE

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DESCRIPTION (Adapted from Applicant's Abstract): Each year 70,000 patients in the United States require open heart surgery to repair or replace a diseased cardiac valve. Many surgeons consider tissue-based artificial heart valves, or bioprostheses, to be the ideal prosthetic valve since they perform well in the short term and od not require chronic anticoagulation. Unfortunately, these valves wear out after about 10-12 years, making them inappropriate for those younger than 65. Many groups have aimed to understand the mechanism of bioprosthetic valve degeneration and improve the valves durability. Valve failure results from calcification and rupture of the prosthetic valve cusps. These modes of failure are now considered two separate forms of degeneration, each with a different mechanism. Our studies have addressed mechanical degeneration, and have focused on understanding the structure/function relationship of aortic valve cusp tissues. Through this research, we have determined that elastin, while composing only 10 percent of the cusp by dry weight, is critical in valve cusp mechanics. We have shown experimentally that damage to elastin leads to a loss of collagen fiber waviness, extension of the valve cusps and reduction in elasticity. These features are typical of the morphologic and mechanical changes observed in explanted bioprosthetic valves. We propose that damage to elastin induces these changes and ultimately leads to fatigue failure of the valve cusps. To provide confirming evidence for this mechanism of valve failure, we propose to carry out the following studies: Hypothesis: The mechanical and morphologic changes observed in explanted xenografts can be simulated by damaging the elastin of porcine aortic valves through controlled incubation in elastase. Specific Aims: We will demonstrate that (i) progressive damage to elastin results in collapse of the spongiosa, elongation of the fibrosa and reduction in the radial extensibility of the valve cusps, (ii) explanted xenograft valves have a reduced extensibility, similar to that of valves with experimentally damaged elastin, (iii) explanted xenograft valves have evidence of elastin damage, and (iv) elastin degeneration in the explants increased with the duration of implantation. Through these proposed studies, we aim to link the degeneration of elastin to the mechanical failure of the explants and confirm this as a key mechanism of bioprosthetic valve degeneration. Once this mechanism is demonstrated, appropriate steps for chemically stabilizing elastin can be explored.