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

Abstract

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.

Glycation and Infiltration of Serum Albumin

“…In this context, the findings presented by Frasca et al. ( 1 ) raise the possibility that circulating levels of glycation products could serve as an early and sensitive marker of SVD, as well as of the risk of BPV failure and reintervention. This potential clinical implication of the results of Frasca et al.…”

“…In the study by Frasca et al. ( 1 ), the proportion of patients with a native bicuspid valve at the time of BPV implantation was not reported, but this factor could have add an effect on the infiltration of glycation products in implanted BPVs. In light of these findings, it is plausible that accumulation of glycation products and HSA within BPV tissues is higher in younger versus older patients, which could therefore contribute to explain the faster SVD observed in younger patients.…”

“…This potential clinical implication of the results of Frasca et al. ( 1 ) needs to be validated in longitudinal cohorts of patients with aortic BPV.…”

“…In this issue of JACC: Basic to Translational Science , Frasca et al. ( 1 ) present the results of an elegant translational research study investigating the possible detrimental effects of infiltrated glycation products and human serum albumin (HSA) leading to disorganization of BPV tissue. The authors demonstrated the presence of infiltrated advanced glycation end products (AGEs) and HSA in: 1) 46 explanted BPVs; 2) BPV bovine pericardium incubated in vitro in glyoxal and HSA; and 3) rat subdermal BPV implants.…”

“…The study of Frasca et al. ( 1 ) cast some light on a novel mechanism that could be targeted by pharmacological therapies or by lifestyle modification. Indeed, the severity of AGE-RAGE–mediated cardiovascular disease can generally be attenuated with decreased AGEs consumption, suppression of RAGE, and increased levels of soluble receptor of RAGE (sRAGE).…”