Perioperative Cardiac Xenograft Dysfunction (PCXD) as a Major Hurdle in the Preclinical (Life-Supporting) Orthotopic (oXTx) Cardiac Xenotransplantation if Compared to the Heterotopic Thoracic (htXTx) Model

Aim:: The perioperative cardiac xenograft dysfunction (PCXD), caused by ischemic crystalloid cardioplegia (Bretschneider) limited survival in a life-supporting orthotopic cardiac pig-to-baboon xenotransplantation model (oXHTx) and was here prevented by a new non-ischemic cold preservation technique. OXTx data of PCXD were compared with our previous heterotopic thoracic (htXTx) model. Another problem of the xenograft “over”growth (XOG) had to be solved with an antiproliferative therapy.

Method: Technique of htXTx (Barnard and Losman's “piggyback heart” technique) was done in 19 baboons (Group G1, 2 with CD40Ab), oXTx in 19 cases using GalKO/hCD46/hTMtg pig hearts. Basic IS consisting of ATG, rituximab, mycophenolate, cortisone and CD40mAb. PCXD as an early cardiac low output in oXTx Group G2 (n = 5) was prevented by a non-ischemic 8oC “Steen's” cold perfusion (CP) with oxygenated blood in a Group G3 (n = 5). As xenograft overgrowth inhibition (XOGI) in a final group G4 (n = 9), antihypertensive drugs and a mTOR inhibitor were given.

Results: When 5 cases of technical failure in htXTx were excluded all recipients were weaned from ECC. In htXTx model, survival was 13 and 35 days with CD40Ab and without 2, 4, 7, 9, 12, 14, 16, 17, 19, 19, 37 up to 50 days. Survival after oXTx was 1 (n = 4), 2 (n = 2), 18, 27, 30, 40 days and in G4 15, 27, 51, 90 (n = 4), 182 and 195 days. Baboons in htXTx group 1 died in 4 cases of delayed xenograft rejection (DXR) and sepsis due to an “over”-IS, in G2 3 died of PCXD. With CP in G3 no PCXD was found and they died of cardiac overgrowth. In G4 combining CP and XOGI 4 baboons survived 90 days and 2 182 and 195 days, 2 died with pCMV+ donor hearts (d15, d27). DXR was not found and all baboons were in excellent general conditions. In G1 (htXTx) PCXD was also observed in a low xenografts pressure (n = 3), but was not relevant, since baboons heart supported during PCXD recovering after 2 days. HtXTx model was limited by a rapid growing pig heart in the small right thorax.

Conclusion: In htXTx, we could also find signs of PCXD indirectly, but was not relevant in hemodynamics and reversible after 48 hours, but in oXTx it was a major problem. A great progress is the CP and XOGI to achieve reproducible long-term survival, which fulfills the ISHLT guidelines (90-days-survival of 60%) for a clinical phase I trial in the next years. In future for XT also other blood cardioplegia techniques from Buckberg, Calafiore or Del Nido should be tested.

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Artikel online veröffentlicht:
03. Februar 2022