Abstract
Despite early realization of the need to control inherent immunogenicity of bioprosthetic replacement heart valves and thereby mitigate the ensuing host response and its associated pathology, including dystrophic calcification, the problem remains unresolved to this day. Concerns over mechanical stiffness associated with prerequisite high cross-link density to effect abrogation of this response, together with the insinuated role of leaching glutaraldehyde monomer in subsequent dystrophic mineralization, have understandably introduced compromises. These have become so entrenched as a benchmark standard that residual immunogenicity of the extracellular matrix has seemingly been relegated to a very subordinate role. Instead, focus has shifted toward the removal of cellular compartment antigens renowned for their implication in the failure of vascularized organ xenotransplants. While decellularization certainly offers advantages, this review aims to refocus attention on the unresolved matter of the host response to the extracellular matrix. Furthermore, by implicating remnant immune and inflammatory processes to bioprosthetic valve pathology, including pannus overgrowth and mineralization, the validity of a preeminent focus on decellularization, in the context of inefficient antigen and possible residual microbial remnant removal, is questioned.
Highlights
Despite deployment of valve heterografts as native valve replacement prostheses more than a half century ago [1], understanding of the specific mechanisms involved in the most pernicious of observed xenogeneic valve substitute pathologies, namely dystrophic mineralization, remains elusive to this day
Moczar et al [15] provided evidence of IgG and complement in 20/22 failed Mitroflow valves, despite the 75% reduction in α-Gal epitope reported by Naso et al While we would concede that the presence of α-Gal, capable of eliciting a host response, may contribute to ensuing pathology of the implanted tissue, it likely does not represent the quintessential xeno-antigen and its depletion should not be held as the sole benchmark for determining xeno-reactivity
Immunoglobulin specific to porcine fibronectin, a structural glycoprotein known to associate with collagen in the extracellular matrix (ECM) and distinctly present in the basement membrane and principally exposed in denuded bioprosthetic valves, persisted in rabbits immunized with tissue cross-linked with a range of GA concentrations spanning and far exceeding those used commercially
Summary
Despite deployment of valve heterografts as native valve replacement prostheses more than a half century ago [1], understanding of the specific mechanisms involved in the most pernicious of observed xenogeneic valve substitute pathologies, namely dystrophic mineralization, remains elusive to this day. Detergent-treated and cross-linked wild-type pericardium, arguably decellularized, resulted in negligible levels of mineralization but which were again significantly increased following preincubation with purified human anti-α-Gal antibody This confirmed the role of tissue-specific immunoglobulin in accelerating calcification of bioprosthetic pericardial tissue in accordance with our rabbit serum pre-incubation study [8], and highlighted the problem of insufficient washout of xeno-antigens following detergent treatment. Manji et al postulate that, provided α-Gal and NeuGc are eliminated in knockout strains of donor pigs, transfer of human genes associated with regulation of complement may suffice to protect against the response to what they term “minor antigens” [26] They further highlighted the need for such genetically engineered bioprosthetic heart valves in children and young patients where structural valve destruction is likely linked to a xenograft-like rejection of the prosthesis [27]. Whether this suggests that leaching of monomeric GA is diminished in acellular tissue, or perhaps is confounded by the presence of the cellular compartment in intact tissue, or both, remains to be determined
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