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).