期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：6
DOI：10.1073/pnas.2120694119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Heart valve disease affects millions, and since there is no effective medical therapy, surgical repair when possible—or more commonly, replacement—are the only treatments available. Bioprosthetic heart valves (BHV), the most frequently used valve replacements, are composed of heterograft tissue, typically fixed in glutaraldehyde, and prepared for human use either as surgically implantable devices or for transcatheter delivery. Protein-glycation limits the durability of BHV, contributing to device failure, often requiring reoperation after only a decade or less of functionality. This problem is addressed by modifying BHV leaflets with poly-2-methyl-2-oxazoline, effectively mitigating glycation and serum protein infiltration and enhancing biocompatibility.
Bioprosthetic heart valves (BHV) fabricated from glutaraldehyde-fixed heterograft tissue, such as bovine pericardium (BP), are widely used for treating heart valve disease, a group of disorders that affects millions. Structural valve degeneration (SVD) of BHV due to both calcification and the accumulation of advanced glycation end products (AGE) with associated serum proteins limits durability. We hypothesized that BP modified with poly-2-methyl-2-oxazoline (POZ) to inhibit protein entry would demonstrate reduced accumulation of AGE and serum proteins, mitigating SVD. In vitro studies of POZ-modified BP demonstrated reduced accumulation of serum albumin and AGE. BP-POZ in vitro maintained collagen microarchitecture per two-photon microscopy despite AGE incubation, and in cell culture studies was associated with no change in tumor necrosis factor-α after exposure to AGE and activated macrophages. Comparing POZ and polyethylene glycol (PEG)–modified BP in vitro, BP-POZ was minimally affected by oxidative conditions, whereas BP-PEG was susceptible to oxidative deterioration. In juvenile rat subdermal implants, BP-POZ demonstrated reduced AGE formation and serum albumin infiltration, while calcification was not inhibited. However, BP-POZ rat subdermal implants with ethanol pretreatment demonstrated inhibition of both AGE accumulation and calcification. Ex vivo laminar flow studies with human blood demonstrated BP-POZ enhanced thromboresistance with reduced white blood cell accumulation. We conclude that SVD associated with AGE and serum protein accumulation can be mitigated through POZ functionalization that both enhances biocompatibility and facilitates ethanol pretreatment inhibition of BP calcification.
关键词：enadvanced glycation end productscalcificationthromboresistanceinflammation
