Noncalcific Mechanisms of Bioprosthetic Structural Valve Degeneration

Abstract

Bioprosthetic heart valves (BHVs) largely circumvent the need for long-term anticoagulation compared with mechanical valves but are increasingly susceptible to deterioration and reduced durability with reoperation rates of ≈10% and 30% at 10 and 15 years, respectively. Structural valve degeneration is a common, unpreventable, and untreatable consequence of BHV implantation and is frequently characterized by leaflet calcification. However, 25% of BHV reoperations attributed to structural valve degeneration occur with minimal leaflet mineralization. This review discusses the noncalcific mechanisms of BHV structural valve degeneration, highlighting the putative roles and pathophysiological relationships between protein infiltration, glycation, oxidative and mechanical stress, and inflammation and the structural consequences for surgical and transcatheter BHVs.

Keywords: bioprosthesis; bioprosthetic heart valve; structural valve degeneration; valve replacement.

Figure 1. Immunohistochemistry of fibrinogen beta chain and plasminogen in valve leaflets dissected from normal and aortic valve stenosis (AS) valves, bioprosthetic valve (BV), and explanted BV (eBV).

Scale bars: 100 μm. Reproduced from Sakaue et al ⁴⁴ under the terms of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

Figure 2. Immunohistochemistry for generalized AGE, CML, glucosepane, and HSA in 2 representative failed clinical BHV alongside unimplanted BHV tissue for both bovine pericardium and porcine aortic valve BHV (scale=100 μm).

Reproduced from Frasca et al ²³ under the terms of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. AGE indicates advanced glycation end‐products; BHV, bioprosthetic heart valve; BP, bovine pericardium; CML, N‐carboxymethyllysine; HSA, human serum albumin; and PAV, porcine aortic valve.

Figure 3. Macro‐scoping images and structural analysis of un‐implanted and explanted bioprosthetic heart valves.

A, Representative unimplanted surgical (Edwards Perimount, top panel) and transcatheter (Edwards SAPIEN XT, bottom panel) bioprosthetic heart valve. B, Second harmonic generation image of unimplanted bioprosthetic heart valve tissue (scale=100 μm). C, Representative failed clinical surgical aortic valve replacement (top two) and transcatheter aortic valve replacement (bottom). D, Micro computed tomography scans and (E) second harmonic generation images of calcified (top row) and noncalcified (bottom 2 rows) failed bioprosthetic heart valve (scale=100 μm). Reproduced from Frasca et al ²³ under the terms of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. SVD indicates structural valve degeneration.

Figure 4. Factors contributing to the noncalcified BHV SVD.

BHV indicates bioprosthetic heart valve; ECM, extracellular matrix; GAGs, glycosaminoglycans; MMPs, metalloproteinases; RNS, reactive nitrogen species; ROS, reactive oxygen species; and SVD, structural valve degeneration.