Calcification and Oxidative Modifications Are Associated With Progressive Bioprosthetic Heart Valve Dysfunction

Abstract

BackgroundBioprosthetic heart valves (BHVs), fabricated from glutaraldehyde‐pretreated bovine pericardium or porcine aortic valves, are widely used for the surgical or interventional treatment of heart valve disease. Reoperation becomes increasingly necessary over time because of BHV dysfunction.Methods and ResultsForty‐seven explanted BHV aortic valve replacements were retrieved at reoperation for clinically severe BHV dysfunction over the period 2010–2016. Clinical explant analyses of BHV leaflets for calcium (atomic absorption spectroscopy) and oxidized amino acids, per mass spectroscopy, were primary end points. Comorbidities for earlier BHV explant included diabetes mellitus and coronary artery bypass grafting. Mean calcium levels in BHV leaflets were significantly increased compared with unimplanted BHV (P<0.001); however, time to reoperation did not differ comparing calcified and noncalcified BHV. BHV dityrosine, an oxidized amino acid cross‐link, was significantly increased in the explants (227.55±33.27 μmol/mol [dityrosine/tyrosine]) but was undetectable in unimplanted leaflets (P<0.001). BHV regional analyses revealed that dityrosine, ranging from 57.5 to 227.8 μmol/mol (dityrosine/tyrosine), was detectable only in the midleaflet samples, indicating the site‐specific nature of dityrosine formation. 3‐Chlorotyrosine, an oxidized amino acid formed by myeloperoxidase‐catalyzed chlorinating oxidants, correlated with BHV calcium content in leaflet explant analyses from coronary artery bypass graft patients (r=0.62, P=0.01) but was not significantly correlated with calcification in non–coronary artery bypass graft explanted BHV.ConclusionsBoth increased BHV leaflet calcium levels and elevated oxidized amino acids were associated with bioprosthesis dysfunction necessitating reoperation; however, BHV calcium levels were not a determinant of implant duration, indicating a potentially important role for oxidized amino acid formation in BHV dysfunction.

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

“…Inflammatory cell aggregates in BHVs tend to be surface oriented, which is reflected by the hematoxylin counterstain of rat explants. It is possible that AGE formation in BHVs provides the opportunity for RAGE signaling and macrophage deposition to produce reactive oxygen species (ROS) that result in OxAA formation in BHV, as demonstrated by our group in both experimental and clinical BHV studies 5,57 . The lack of demonstrable glucosepane in the rat subcutaneous explants versus virtually all the clinical explants may be due to short (30-day) implantation times relative to the physiologic formation time of glucosepane, which proceeds through long-lived Amadori intermediates 12,53,58 .…”

“…This process is driven by cellular, biochemical, and biomechanical mechanisms arising from valve properties and design, patient characteristics, and the interactions between them. Calcification is observed in the majority of SVD cases; however, approximately 30% of SVD cases are not associated with significant calcification [5][6][7] . Further, recent observation suggests that calcification might be associated with SVD without necessarily being functionally causative 5 .…”

“…Calcification is observed in the majority of SVD cases; however, approximately 30% of SVD cases are not associated with significant calcification [5][6][7] . Further, recent observation suggests that calcification might be associated with SVD without necessarily being functionally causative 5 . Several noncalcific mechanisms have been proposed to contribute to SVD, including inflammatory oxidation, tissue thickening, and collagen network degeneration 4,8 .…”

Deterioration of Glutaraldehyde Crosslinked Heterograft Biomaterials due to Advanced Glycation End Product Formation and Serum Albumin Infiltration

“…A) 14 C-glucose (100mM) uptake by BP with and without the presence of BSA (5%). * p<0.001 B) 14 C-glucose (100mM) uptake by CS with and without the presence of BSA (5%).…”

“…However, this yielded only incremental improvements in BHV lifespan [10][11][12][13]. Prior studies of explanted BHV showed that the degree of calcification does not completely explain SVD, and that approximately 25% of failed valves lack any significant calcification [14].…”