Progress in CardiologyPorcine bioprosthetic heart valves: The next generation
Section snippets
Rheumatic heart disease—a global problem
Valvular heart disease is one of the most common problems facing children and young adults worldwide. In the developed world, young patients typically have valvular heart disease (as opposed to coronary artery disease). In the developing world, there is a high incidence of rheumatic heart disease, often in young patients, which is associated with a reasonably high mortality rate. Globally (although the majority is in the developing world), the number of patients with rheumatic heart disease is >
Mechanical prostheses
Mechanical valves have the advantage of long-term durability but require lifelong, closely regulated anti-coagulation, with risks of thrombosis, thromboembolism, or spontaneous bleeding, any of which can be fatal. They are, therefore, less than ideal, particularly in young patients and in patients in the developing world, where close monitoring of anticoagulation may be difficult.
With mechanical valve replacement, the cumulative annual risk of bleeding (associated with therapeutic
Bioprosthetic prostheses
Bioprosthetic heart valves are constructed from porcine heart valves or from bovine pericardium that have been glutaraldehyde treated to help preserve the tissues and decrease their immunogenicity.2, 7 Importantly, BHVs do not require anticoagulation, negating its associated complications. However, structural deterioration is a significant problem, which may necessitate replacement of the bioprosthesis. Repeat cardiac surgery is associated with a 2- to 3-fold higher risk of death than the
Histopathology of inflammation/rejection in failed BHVs
Some of the earliest reports of inflammatory changes in explanted BHVs were in children and young adults (2-20 years) whose valves failed within 4 years. Evidence of pseudointimal proliferation, with fibrocalcific and thrombotic changes on microscopic examination, was reported.2, 12, 13, 14, 15 Similar early failure demonstrating features of inflammation and thrombosis (with fibrin deposition causing obstruction) was seen in young-to-middle-aged adults within 4 years (sometimes within months)
Link between inflammation and calcification
There are a number of other animal studies that suggest a link between inflammation/thrombogenicity/coagulation and calcification. Schussler et al23 demonstrated that glutaraldehyde had a protective effect against the humoral response, but itself elicited a xenogeneic cellular response. Human and Zilla24 suggested a role for circulating graft-specific antibody in causing BHV calcification. Dahm et al,25 using enzyme-linked immunosorbent and lymphocyte proliferation assays, provided evidence
The galactose-α1,3-galactose antigen/anti–galactose-α1,3-galactose antibody barrier
The initial problem faced in pig-to-nonhuman primate solid organ xenotransplantation was hyperacute rejection. This is initiated by the binding of preformed natural antibodies to antigens on porcine endothelial cells, leading to complement deposition and endothelial cell activation, resulting in graft thrombosis, interstitial hemorrhage and edema, ischemia, and organ failure.31
The most important target pig antigen is galactose-α1,3-galactose (Gal).32 Anti-Gal antibodies are present in mammals
Extrapolating advances from live tissue/organ xenotransplantation to BHV implantation
Bioprosthetic heart valves are not live tissues because they have been glutaraldehyde fixed, and thus, intrinsic endothelial cell activation (and its consequent detrimental sequelae) is not induced. Nevertheless, if prepared from wild-type (ie, genetically unmodified) pigs, surface antigens, for example, Gal, incite an immune response, as do other decellularized tissues from these pigs.46 There are clearly similarities between the pathologic features of explanted BHVs from patients and those
Implications for clinical valve replacement
The above studies have significant implications for clinical valve replacement. With the technological advances that are taking place in the development of genetically engineered pigs, it may soon be possible to breed pigs that have heart valves considered ideal for implantation into humans. Genetically modified pigs could provide a source of BHVs that do not deteriorate structurally or calcify, or at least where these processes are greatly slowed. Because the valves would be protected, at
Economic considerations
If BHVs could be fashioned to provide prolonged survival in young patients and in patients in whom long-term anticoagulation is contraindicated, there could be a worldwide paradigm shift in valve replacement. The biggest hurdle to the use of genetically engineered pigs as sources of BHVs would then be related to economics. If a BHV from a genetically engineered pig functioned in the patient for a significantly longer period, this would clearly be in the patient's interests but could be
Conclusions
There is substantial evidence pathologically, immunohistochemically, and in small animal studies that an immune reaction develops to glutaraldehyde-fixed xenograft tissue, for example, BHVs. Although it is not possible to conclusively determine the contribution of “wear-and-tear” vs immune-mediated damage, the severity of the immune reaction correlates with the extent of calcification in the xenograft tissue. It is the same calcific degeneration that leads to failure of BHVs in humans. The
Disclosures
The authors have no financial or other conflict of interest.
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Cited by (79)
Biomimetic-modified bioprosthetic heart valves with Cysteine-Alanine-Glycine peptide for anti-thrombotic, endothelialization and anti-calcification
2023, International Journal of Biological MacromoleculesChitosan/hyaluronic acid polyanion bilayer applied from carbon acid as an advanced coating with intelligent antimicrobial properties for improved biological prosthetic heart valves
2022, International Journal of Biological MacromoleculesInflammation-triggered dual release of nitroxide radical and growth factor from heparin mimicking hydrogel-tissue composite as cardiovascular implants for anti-coagulation, endothelialization, anti-inflammation, and anti-calcification
2022, BiomaterialsCitation Excerpt :The aldehyde groups and carboxy groups existing in Glut-PP can bind to calcium ions and lead to calcium deposition. Upon implantation, macrophages infiltrate HT, secreting cytokines and other chemoattractants to recruit more inflammatory cells to attack the foreign materials [26,67,68]. The degree of inflammation has been reported to correlate with calcification [69].
Zwitterionic hydrogel-coated heart valves with improved endothelialization and anti-calcification properties
2021, Materials Science and Engineering CCitation Excerpt :Due to the urgent need for valve replacement surgery, BHVs has become one major type of valve substitutes for the last half-century. Despite the superior properties of BHVs, BHVs may still suffer from deterioration and dysfunction due to the inevitable calcification [32]. Currently, most of commercial BHVs products are crosslinked with GA, which is benefit for stabilizing the heart valves.
Poorly suited heart valve prostheses heighten the plight of patients with rheumatic heart disease
2020, International Journal of Cardiology
Work on xenotransplantation in the Thomas E. Starzl Transplantation Institute of the University of Pittsburgh is supported, in part, by National Institutes of Health grant nos. U19 AI090959, U01 AI068642, and R21 A1074844 and by Sponsored Research Agreements between the University of Pittsburgh and Revivicor, Inc, Blacksburg, VA. Burcin Ekser, MD, is a recipient of a National Institutes of Health NIAID T32 AI 074490 Training Grant. However, none of this funding was used to support the preparation of this manuscript. The authors have no financial or other conflict of interest and are solely responsible for the drafting and editing of the manuscript and its final contents.