Thorac Cardiovasc Surg 2015; 63 - OP167
DOI: 10.1055/s-0035-1544419

The Heterotopic Thoracic Cardiac Xenotransplantation Model (Pig-to-baboon) in Two Different Groups without and with an Additional Myelodepressive Regime

P. Brenner 1, J.-M. Abicht 2, S. Guethoff 1, S. Buchholz 1, T. Mayr 1, A. Bauer 2, S. Blank 3, B. Kessler 4, E. Wolf 4, C. Becker 5, D. Ayares 6, C. McGregor 7, C. Belka 8, C. Hagl 1, B. Reichart 1
  • 1Department of Cardiac Surgery, Klinikum Grosshadern der LMU, Munich, Germany
  • 2Department of Anesthesiology, Klinikum Grosshadern der LMU, Munich, Germany
  • 3Walter-Brendel-Centre of the LMU, Munich, Germany
  • 4Institute of Molecular Animal Breeding and Biotechnology, Munich, Germany
  • 5Department of Clinical Radiology, Munich, Germany
  • 6Revivicor Inc., Blackburg, United States
  • 7Department of Cardiothoracic Surgery, London, United Kingdom
  • 8Department of Radiation Oncology, Munich, Germany

Background: In a worldwide first model of the heterotopic thoracic cardiac xenotransplantation under working heart conditions (htHXTx, group G1) we introduced for the first time an additional preoperative myelosuppressive treatment regime from plasmocytoma therapy in a new group G2. A further reduction of antibody-producing cells should be achieved by irradiation of total thoracic and abdominal lymph nodes with 7 Gray (Gy) one week after htHXTx in the pig-to-baboon model.

Methods: In two groups of recipient baboons (G1: n = 10, G2: n = 9 with additional myelosuppression) we tested two different immunomodulatory strategies. Double- or triple-transgenic pig hearts (GalT-KO/hCD46/±hTM) were used as donors. HtHXTx was performed according to the technique of Barnard and Losman. In both groups basic immunosuppression consisted of Tacrolimus, Mycophenolate and steroids. Rituximab was administered 4 and 2 weeks before htHXTx and ATG the first p.o. days. Immunoadsorption (IA, Ig-Theraflex column, Life18 system) was performed twice, two days pre-transplant and on d0. Human anti-CMV-IgG was given after each IA. In case of rejection, high dose steroids, ATG or Bortezomib were administered in combination with repeated IA. In G2 additionally cyclophosphamide and steroids were given every of 4 weeks before htHXTx and the lymph node irradiation with 7 Gy was performed on day 7.

Results: When excluding baboons with perioperaticve technical failures (n = 4 in each group) the mean survival time was 22 ± 5.7 days in G1 (maximum survival of 50 days) and 22 ± 5.8 days in G2 (max. survival: 37 days). Overall survival (with technical failures) in G1 was 14 ± 4.6 days and 14 ± 3.9 days in G2. By IA IgG antibodies were reduced by 80% in the recipients. Whereas in G1 cause of death were treatment resistant delayed humoral xenograft rejection (DHXR, n = 3) and overtreatment (n = 3), in G2 only one DHXR occurred and most baboons died of p.o. problems like pneumothorax, renal failure, lung edema, sepsis and apoplex.

Conclusion: A myelosuppressive regime could reduce in our htHXTx group G2 DHXR by 60% (20% of baboons in G2 in contrast to 50% in G1). A further prolongation of the survival time must be achieved by a better"fine-tuning“ of immunosuppression, shortening of the pretreatment period from 4 to 1 week without steroids and additional reduction of technical complication rate (often caused by the long preoperativ steroid pre-treatment) before going to a clinic application.