Immunological
Recently, research has brought new insights on the inflammatory and immunological role in bioprosthesis dysfunction, describing immune rejection also as a cause for bioprosthesis failure (43, 44).
In all biological processes, immune responses have several grades, from a physiological to pathologic state. Even in the setting of a bioprosthesis, inflammation can be divided into several types: 1) the postsurgical normal wound healing; 2) nonspecific innate inflammatory reaction to a new foreign body; and 3) immune-mediated rejection and/ or inflammation (64–66). We will focus on point 2 and 3, since the normal postsurgical wound healing is not in the scope of this review.
Despite all the fixation and processing procedures, Glut decreases but not entirely eliminates the antigenicity of tissue valves (67). Collagen matrix (with cell debris and necrotic products) elicits a strong nonspecific inflammatory response, including infiltration by macrophages and eosinophils, followed by a lymphocyte T response (68). Persistent antigenicity of bioprosthesis has been shown to continually stimulate graft-specific adaptive immune reactions with important biomaterial dysfunction (68). The dysfunctional endothelial layer may also contribute to maintain the inflammatory status, probably through the reduced nitric oxide production and increased generation of reactive oxygen species and inflammatory cytokines (69).
Glut itself also causes some degree of inflammation (70). Additionally, inflammation and calcification are also linked. It has been shown that calcification is associated with the amount of inflammation, as lymphocytes and macrophages produce osteopontin (an important cytokine in the calcification process) (70). Inflammatory and fibroblast signaling contribute to a pro-osteogenic environment (with the activation of quiescent VIC to the osteogenic VIC phenotype) and remodeling process, predisposing dystrophic calcification (71).
Host cardiovascular risk factors may also contribute to the inflammatory environment. Studies have demonstrated that some risk factor such dyslipidemia, diabetes or metabolic syndrome may modulate bioprosthesis degeneration through inflammation (53, 54). Analyzes from the explanted prosthesis have also revealed that explants are usually infiltrated by oxidized low-density lipoproteins (LDL), beside inflammatory cells (74). Indeed, patients with SVD have a tendency of higher triglyceride levels and high levels of small, dense LDL, which are associated with prosthesis dysfunction (74). Moreover, Mahmut et al. have shown that lipoprotein-associated phospholipase A2 (Lp-PLA2), an enzyme that produces pro-inflammatory substances from LDL, is an independent predictor of SVD (75).
Another important factor that has recently been associated with bioprosthetic valve dysfunction is Alpha-gal. Alpha-gal (galactose-alpha-1,3-galactose) is a carbohydrate found in most mammalian membranes, but not in humans. Humans normally display anti-gal antibodies due to antigenic stimulation, representing an important barrier to xenotransplantation (76). Yet, alpha-gal epitopes are present in bioprosthesis, even in decellularized tissues. It has been shown that the implantation of bioprosthesis induce a specific immune reaction to the alpha-gal antigen, with the production of anti-alpha-gal antibodies (76). The interaction between the circulation anti-alpha gal antibodies and calcification of bioprosthesis has been established (58, 59), but the contribution to long-term dysfunction is not yet completely understood. However, basic research continues and recent studies have shown that engineered pericardial tissue from alpha-gal-deficient pigs calcify less in animal models (78). Tissue valve investigation continues in order to design new tissues with less alpha-gal epitopes, and a genetically modified pig with no expression of alpha-gal has already been generated, but more studies are needed (79).