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Consistent success in life-supporting porcine cardiac xenotransplantation

An Author Correction to this article was published on 03 April 2019

This article has been updated

Abstract

Heart transplantation is the only cure for patients with terminal cardiac failure, but the supply of allogeneic donor organs falls far short of the clinical need1,2,3. Xenotransplantation of genetically modified pig hearts has been discussed as a potential alternative4. Genetically multi-modified pig hearts that lack galactose-α1,3-galactose epitopes (α1,3-galactosyltransferase knockout) and express a human membrane cofactor protein (CD46) and human thrombomodulin have survived for up to 945 days after heterotopic abdominal transplantation in baboons5. This model demonstrated long-term acceptance of discordant xenografts with safe immunosuppression but did not predict their life-supporting function. Despite 25 years of extensive research, the maximum survival of a baboon after heart replacement with a porcine xenograft was only 57 days and this was achieved, to our knowledge, only once6. Here we show that α1,3-galactosyltransferase-knockout pig hearts that express human CD46 and thrombomodulin require non-ischaemic preservation with continuous perfusion and control of post-transplantation growth to ensure long-term orthotopic function of the xenograft in baboons, the most stringent preclinical xenotransplantation model. Consistent life-supporting function of xenografted hearts for up to 195 days is a milestone on the way to clinical cardiac xenotransplantation7.

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Fig. 1: Survival, laboratory parameters, necropsy and histology after orthotopic xenotransplantation.
Fig. 2: Quantitative evaluation of antibodies, complement and fibrin in myocardial tissue and serum levels of non-galactose-α1,3-galactose xenoreactive antibodies.

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Change history

  • 03 April 2019

    In this Letter, Mayuko Kurome and Valeri Zakhartchenko have been added to the author list (affiliated with Institute of Molecular Animal Breeding and Biotechnology, Gene Center, LMU Munich, Munich, Germany). The author list and ‘Author contributions’ section have been corrected online; see accompanying Amendment.

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Acknowledgements

We thank the Walter Brendel Centre of Experimental Medicine, Munich for support and provision of facilities, especially U. Pohl, M. Shakarami and all animal caretakers. Financial support was provided by the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG) TRR 127. We acknowledge K. Reimann for providing the CD40 monoclonal antibody for the experiments.

Reviewer information

Nature thanks C. Knosalla and J. Madsen for their contribution to the peer review of this work.

Author information

Affiliations

Authors

Contributions

B.R., P.B., T.M., M.L. and J.-M.A. conceived and led the study; M.L., T.M., B.R., R.E., R. Herzog, S.G., S.B., S.M., A.D., A. Bauer, F.W., M. Mihalj, A. Panelli, L.I., J.Y., A.K.F., L.Q., C.H., I.L., I.B., M. Mokelke, J.R., P.B. and J.-M.A. performed the experiments and collected samples; S.S., T.S., A. Paskevicius and L.Q. performed non-ischaemic heart preservation experiments; M.L., A. Panelli, A. Bauer and J.-M.A. performed haemodynamic and echocardiographic analyses; R.S. and R.R. provided immunological analyses; E.K., K.K., R. Hinkel and C.K. performed histochemical analyses; M.D. and E.W. provided protein analysis; A.F. and S.R. performed necropsy and histological analyses with contributions from T.M. and A. Panelli; M.L., T.M., B.R., R.S., R.R., R. Hinkel, M.D. and J.-M.A. analysed the data; A. Baehr, S.E., B.K., M.K., V.Z., D.A., E.W. and N.K. provided genetically multi-modified donor pigs; U.S. and F.-J.K. provided non-human primates; U.B., G.W. and A.S. developed PASylated anti-CD40L Fab; B.R., M.L., T.M. and J.-M.A. wrote the manuscript; A.K., A.S., R.R., S.S., R. Hinkel, P.B. and E.W. reviewed and edited the manuscript.

Corresponding author

Correspondence to Bruno Reichart.

Ethics declarations

Competing interests

D.A. is chief executive officer and chief scientific officer of Revivicor. Inc. A.S. and U.B. are cofounders of XL-protein GmbH, Germany. The other authors declare no competing interests.

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Extended data figures and tables

Extended Data Fig. 1 Haemodynamic data, measured by transpulmonary thermodilution and post-operative catecholamine support.

Measurements were taken after induction of anaesthesia (before) and 60 min after termination of CPB (after). Donor hearts of group I (black) received crystalloid cardioplegia, donor hearts of groups II (red) and III (magenta) were preserved with continuous cold hyperoncotic perfusion; data are presented as scatter plots with mean ± s.d. with individuals shown as dots; n = 14 animals, two-sided paired and unpaired t-tests, P values as indicated. a, Stroke volume index. b, Cardiac index before and after CPB. Both parameters decreased in group I and were lower in group I after CPB than in group II and III. c, Dosages of catecholamines 60 min after termination of CPB. d, Durations of post-operative vasopressive and inotropic support. Animals in group I required more noradrenaline and adrenaline than those in group II and III. Animals in group I required inotropic support with adrenaline for a longer time.

Source data

Extended Data Fig. 2 Graphics of left ventricular sizes during diastole and systole that were derived from transthoracic echocardiography.

Left, diastole; right, systole. a, Animal 9 (group II, survival 40 days): left ventricular mass had increased by 303% on day 38, left ventricular function was severely impaired because of myocardial hypertrophy and decreased left ventricular filling volume. Left ventricular fractional shortening measurements were 32% and 14% on day 1 and 38. b, Animal 11 (group III, survival 90 days): in contrast to animal 9, left ventricular mass had increased by only 22% on day 82, left ventricular function was preserved. Left ventricular fractional shortening measurements were 27% and 34% on day 1 and 82. c, Pig 5157 (control, donor sibling of the pig whose heart was transplanted in animal 9): left ventricular mass had increased by 187% on day 33, left ventricular function was preserved. Left ventricular fractional shortening measurements were 32% and 41% on day 1 and 33. Compared to 9 (a), the left ventricle had grown less in size and showed no hypertrophy.

Extended Data Fig. 3 Additional laboratory parameters.

a, b, Serum concentrations of lactate dehydrogenase (a) and platelet counts (b) in animals of groups I (black), II (red) and III (magenta). At the end of experiments in groups I and II, platelet counts decreased whereas LDH increased. Group III animals did not show these alterations.

Source data

Extended Data Fig. 4 Immunofluorescence staining of myocardial tissue.

ad, Immunofluorescence staining of myocardial sections from group I (3; left row), group II (9; middle row) and group III (11, right row) for IgM (a), IgG (b), C3b/c (c; red), C4b/c (c; green) and fibrin (d); nuclei were stained with DAPI (blue). Scale bars, 25 μm. n = 1, group I; n = 3, group II; n = 5, group III; one representative biological sample per group is shown.

Extended Data Fig. 5 Immunohistochemistry of post-mortem myocardial specimens.

a, b, Expression of human membrane cofactor protein (hCD46) (a) and human thrombomodulin (hTM) (b) was consistent in all donor organs (1–14). Scale bars, 50 μm. n = 14 GTKO/hCD46/hTM pigs; n = 1 wild-type pig (control). Biological samples from all animals are shown.

Extended Data Table 1 Immunosuppressive regimen, anti-inflammatory and additive therapy with corresponding doses and timing intervals

Supplementary information

Supplementary Figure 1

This file contains gel source data.

Reporting Summary

Video 1

Transthoracic echocardiographic midpapillary short axis view of porcine graft after cardiac xenotransplantation. Experiment 9 (group II, day 30): increased LV wall thickness and reduced LV filling volume indicating myocardial hypertrophy. LV function was impaired.

Video 2

Transthoracic echocardiographic midpapillary short axis view of porcine graft after cardiac xenotransplantation. Experiment 11 (group III, day 57): normal LV wall thickness and normal LV filling volume. LV function was preserved.

Video 3

Transthoracic echocardiographic midpapillary short axis view of porcine graft after cardiac xenotransplantation. Experiment 14 (group III, day 180): increased LV wall thickness, but normal LV filling volume. LV function was preserved.

Source data

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Längin, M., Mayr, T., Reichart, B. et al. Consistent success in life-supporting porcine cardiac xenotransplantation. Nature 564, 430–433 (2018). https://doi.org/10.1038/s41586-018-0765-z

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Keywords

  • Human Thrombomodulin
  • Human Membrane Cofactor Protein
  • Terminal Cardiac Failure
  • Xenografted
  • Left Ventricular (LV)

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