Abstract 13187: Inhibition of Advanced Glycation End Products Formation and Serum Protein Infiltration in Bioprosthetic Heart Valves: Investigations of Anti-Glycation Agents

Abstract

Introduction: Bioprosthetic heart valves (BHV) fabricated from glutaraldehyde pretreated bovine pericardium (BP), are the most commonly used heart valve replacements. However, BHV durability is limited by structural valve degeneration (SVD) resulting from both calcification and advanced glycation end product (AGE) deposition together with serum protein infiltration. This study investigated, for the first time, the application of anti-glycation agents as a way to mitigate AGE-related structural degeneration of BHV. Hypothesis: We investigated the hypothesis that anti-AGE agents (Aminoguanidine (AG), Pyridoxamine (PYR), and N-Acetylcysteine (NAC)) could mitigate BP glycation in model studies, both in vitro and in vivo. Methods: To model AGE accumulation in BHV, we used well-established accelerated in vitro glycation models using BP incubation with or without inhibitors. Incorporation of AGE in BP was monitored using radiolabeled glycation precursors. Changes in collagen structure were examined by two photon confocal microscopy and differential scanning calorimetry. In vivo studies used a juvenile rat subdermal BP implantation model with drug administration via drinking water. Endpoints were AGE formation, collagen structure, thermal denaturation temperature, serum albumin uptake, calcification, and serum glycation marker levels. Results: In vitro studies demonstrated that each of these agents significantly inhibited AGE formation in BP. However, after 28-day rat subdermal BP implantation in vivo, only PYR demonstrated significant inhibition of both AGE and serum albumin accumulation per immunostaining. BHV calcification was not mitigated by PYR, AG or NAC. Conclusions: This study is the first to demonstrate the use of AGE inhibitors in mitigating BHV glycation. PYR demonstrated significant efficacy both in vitro and in vivo, mitigating AGE formation and albumin infiltration in BP. Thus, this study provides a rationale for investigating PYR as a possible candidate for improving the durability and biocompatibility of clinically used BHV, providing the solution for this unmet clinical need.