Glycation and Serum Albumin Infiltration Contribute to the Structural Degeneration of Bioprosthetic Heart Valves

Background: Bioprosthetic heart valves (BHV) are widely used to treat heart valve disease but are fundamentally limited by structural valve degeneration (SVD). Non-calcific mechanisms of SVD entirely account for approximately 30% of SVD cases and contribute to calcific SVD, but remain understudied. Glycation mechanisms have not been previously associated with SVD, despite being established as degenerative in collagenous native tissues. Objectives: To determine whether blood component infiltration-based glycation and concomitant human serum albumin (HSA) deposition contribute mechanistically to SVD. Methods: Immunohistochemistry (IHC) was used to identify advanced glycation end-products (AGEs) and serum albumin accumulation in 45 aortic valve BHV explanted due to SVD, glutaraldehyde-treated bovine pericardium (BP) incubated in vitro in glyoxal and HSA, and rat subcutaneous BP implants. Structural impacts of glycation-related mechanisms were evaluated by second harmonic generation (SHG) collagen imaging. Hydrodynamic effects of valve glycation and concomitant HSA exposure were studied with an ISO-5840-compliant pulse duplicator system using surgical grade BHV. Results: All 45 clinical explants and in vitro-incubated BP demonstrated accumulated AGE and HSA compared to un-implanted, un-exposed BHV. SHG revealed instigation of collagen malalignment similar to that in SVD explants by glycation and HSA infiltration. Rat subdermal explants also showed AGE and serum albumin accumulation. Pulse duplication demonstrated significantly reduced orifice area and increased pressure gradient and peak fluid velocity following glyoxal and HSA incubations. Conclusions: Glycation and concomitant HSA infiltration occur in clinical BHV and contribute to structural and functional degeneration of leaflet tissue, thus representing novel, interacting mechanisms of BHV SVD.