Elsevier

American Heart Journal

Volume 164, Issue 2, August 2012, Pages 177-185
American Heart Journal

Progress in Cardiology
Porcine bioprosthetic heart valves: The next generation

https://doi.org/10.1016/j.ahj.2012.05.011Get rights and content

There have been significant advances in organ xenotransplantation (cross-species transplantation), especially in the development of genetically engineered pigs, but clinical trials of solid organ transplants are still a time away. However, there is a form of pig-to-human xenotransplantation that has been taking place since the 1960s—bioprosthetic heart valve (BHV) replacement. Recently, there has been increasing evidence that, despite glutaraldehyde fixation of BHVs, there is a significant immune reaction to the valves, leading to calcification, rapid structural deterioration, and failure, particularly in young patients who have a more vigorous immune system and metabolism than the elderly. However, it is the young patients who would most benefit from such BHVs because these avoid the complications associated with the lifelong anticoagulation required with mechanical valves.

In this review, we examine pathologic and immunohistochemical reports of failed BHVs that suggest that there is an immune response to these valves. Small animal studies that link the development of calcification and BHV failure to the immune response are reviewed. We draw parallels between the problems of glutaraldehyde-fixed tissue xenotransplantation and those currently being faced in live organ xenotransplantation. Finally, we discuss the advances being made in the production of genetically modified pigs and the evidence that these pigs may become a source of BHVs that can be used worldwide to treat valvular heart disease in children and young adults (for whom there is no ideal valve replacement in existence today). The design of a BHV that is resistant to the host's immune response would be a major step forward in cardiac surgery.

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.

References (52)

  • M. Dahm et al.

    Immunogenicity of glutaraldehyde-tanned bovine pericardium

    J Thorac Cardiovasc Surg

    (1990)
  • A. Vincentelli et al.

    Does glutaraldehyde induce calcification of bioprosthetic tissues?

    Ann Thorac Surg

    (1998)
  • D.K. Cooper et al.

    Identification of alpha-galactosyl and other carbohydrate epitopes that are bound by human anti-pig antibodies: relevance to discordant xenografting in man

    Transpl Immunol

    (1993)
  • R.A. Manji et al.

    Human ABO blood group is important in survival and function of porcine working hearts

    Am J Transplant

    (2003)
  • B. Ekser et al.

    Clinical xenotransplantation—the next medical revolution?

    Lancet

    (2012)
  • D.K. Cooper et al.

    Will the pig solve the transplantation backlog?

    Annu Rev Med

    (2002)
  • D. Lloyd-Jones et al.

    Executive summary: heart disease and stroke statistics—2010 update: a report from the American Heart Association

    Circulation

    (2010)
  • R.F. Siddiqui et al.

    Bioprosthetic heart valves: modes of failure

    Histopathology

    (2009)
  • M. Ruel et al.

    Very long-term survival implications of heart valve replacement with tissue versus mechanical prostheses in adults < 60 years of age

    Circulation

    (2007)
  • M.B. Leon et al.

    Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery

    N Engl J Med

    (2010)
  • D.T. Simionescu

    Prevention of calcification in bioprosthetic heart valves: challenges and perspectives

    Expert Opin Biol Ther

    (2004)
  • E. Diaz-Jauanen et al.

    Studies of human lymphocytes in the newborn and the aged

    Am J Med

    (1975)
  • W.M. Talbert et al.

    Acute aortic stenosis of a porcine valve heterograft apparently caused by graft rejection: case report with discussion of immune mediated host response

    Tex Heart Inst J

    (1982)
  • D.C. Miller et al.

    The durability of porcine xenograft valves and conduits in children

    Circulation

    (1982)
  • A. Carpentier

    Valvular xenograft and valvular xenobioprosthesis: past, present, and future

    Adv Cardiol

    (1980)
  • J.P. Camilleri et al.

    Structural changes of glutaraldehyde-treated porcine bioprosthetic valves

    Arch Pathol Lab Med

    (1982)
  • Cited by (79)

    • Inflammation-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, Biomaterials
      Citation 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 C
      Citation 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.

    View all citing articles on Scopus

    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.

    View full text