Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2020 May;109(5):1357-1361.
doi: 10.1016/j.athoracsur.2019.08.090. Epub 2019 Oct 4.

Early Experience With Preclinical Perioperative Cardiac Xenograft Dysfunction in a Single Program

Laura DiChiacchio  1 , Avneesh K Singh  2 , Billeta Lewis  2 , Tianshu Zhang  2 , Naomi Hardy  3 , Chetan Pasrija  1 , David Morales  1 , Patrick Odonkor  1 , Erik Strauss  1 , Brittney Williams  1 , Kristopher B Deatrick  1 , David J Kaczorowski  1 , David Ayares  4 , Bartley P Griffith  1 , Stephen T Bartlett  1 , Muhammad M Mohiuddin  5
Affiliations

Early Experience With Preclinical Perioperative Cardiac Xenograft Dysfunction in a Single Program

Laura DiChiacchio et al. Ann Thorac Surg. 2020 May.

Abstract

Background: Perioperative cardiac xenograft dysfunction (PCXD) was described by McGregor and colleagues as a major barrier to the translation of heterotopic cardiac xenotransplantation into the orthotopic position. It is characterized by graft dysfunction in the absence of rejection within 24 to 48 hours of transplantation. We describe our experience with PCXD at a single program.

Methods: Orthotopic transplantation of genetically engineered pig hearts was performed in 6 healthy baboons. The immunosuppression regimen included induction by anti-CD20 monoclonal antibodies (mAb), thymoglobulin, cobra venom factor, and anti-CD40 mAb, and maintenance with anti-CD40 mAb, mycophenolate mofetil, and tapering doses of steroids. Telemetry was used to assess graft function. Extracorporeal membrane oxygenation was used to support 1 recipient. A full human clinical transplantation team was involved in these experiments and the procedure was performed by skilled transplantation surgeons.

Results: A maximal survival of 40 hours was achieved in these experiments. The surgical procedures were uneventful, and all hearts were weaned from cardiopulmonary bypass without issue. Support with inotropes and vasopressors was generally required after separation from cardiopulmonary bypass. The cardiac xenografts performed well immediately, but within the first several hours they required increasing support and ultimately resulted in arrest despite maximal interventions. All hearts were explanted immediately; histology showed no signs of rejection.

Conclusions: Despite excellent surgical technique, uneventful weaning from cardiopulmonary bypass, and adequate initial function, orthotopic cardiac xenografts slowly fail within 24 to 48 hours without evidence of rejection. Modification of preservation techniques and minimizing donor organ ischemic time may be able to ameliorate PCXD.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
Non-Gal Antibody Assay: Anti pig non-Gal (A) IgG and (B) IgM antibody levels in mean fluorescence intensity (MFI) were measured in cardiac xenograft baboon recipient’s serum by flow cytometry using GTKO porcine endothelial cells. MFI was normalized with respect to positive control serum as one hundred.
Figure 2.
Figure 2.
Hematoxylin and eosin staining from right atrium (representative) of xenograft with necrosis and without any sign of rejection or microthrombosis.
See this image and copyright information in PMC

References

    1. Mohiuddin MM, Singh AK, Corcoran PC, Thomas ML 3rd, Clark T, Lewis BG, Hoyt RF, Eckhaus M, Pierson RN 3rd, Belli AJ, Wolf E, Klymiuk N, Phelps C, Reimann KA, Ayares D, Horvath KA. Chimeric 2C10R4 anti-CD40 antibody therapy is critical for long-term survival of GTKO.hCD46.hTBM pig-to-primate cardiac xenograft. Nat Commun. 2016April5;7:11138. - PMC - PubMed
    1. Thompson P, Cardona K, Russell M, Badell IR, Shaffer V, Korbutt G, Rayat GR, Cano J, Song M, Jiang W, Strobert E, Rajotte R, Pearson T, Kirk AD, Larsen CP. CD40-specific costimulation blockade enhances neonatal porcine islet survival in nonhuman primates. Am J Transplant. 2011;11:947–957. 3. - PMC - PubMed
    1. Mohiuddin MM, Corcoran PC, Singh AK, Azimzadeh A, Hoyt RF Jr, Thomas ML, Eckhaus MA, Seavey C, Ayares D, Pierson RN 3rd, Horvath KA. B cell depletion ex tends the survival of GTKO.hCD46Tg pig heart xenografts in baboons for up to 8 months. Am J Transplant. 2012;12:763–771. - PMC - PubMed
    1. Singh AK, Chan JL, DiChiacchio L, Hardy NL, Corcoran PC, Lewis BGT, Thomas ML, Burke AP, Ayares D, Horvath KA, Mohiuddin MM. Cardiac xenografts show reduced survival in the absence of transgenic human thrombomodulin expression in donor pigs. Xenotransplantation. 2018October5:e12465. - PMC - PubMed
    1. Byrne GW, McGregor CG. Cardiac xenotransplantation: progress and challenges. Curr Opin Organ Transplant. 2012April;17(2):148–54. doi: 10.1097/MOT.0b013e3283509120. - DOI - PMC - PubMed

Substances