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Organ Xenotransplantation: Heart & Lung

Thursday September 23, 2021 - 15:00 to 16:15

Room: General Session

115.3 Ischemia minimization significantly reduces pig myocardial injury during human blood perfusion in an ex vivo working heart model

Franziska Pollok, United States

Postdoctoral Research Fellow
Center for Transplantation Sciences
Massachusetts General Hospital


Ischemia minimization significantly reduces pig myocardial injury during human blood perfusion in an ex vivo working heart model

Franziska Pollok1,2, Margaret R. Connolly1, Anthony Calhoun1, Zahra A. Habibabady1, Shuhei Miura1, Madelyn Ma1, Shannon G. Pratts1, Yinan Kan3, Jacob V. Layer3, Ellie Tan3, Ranjid Anand3, Mailin Li3, Katherine C. Hall3, Michele E. Youd3, Kathryn Stiede3, Wenning Qin3, Mike Curtis3, Wes F. Westin3, Lars Burdorf1, Agnes M. Azimzadeh1, Richard N. Pierson III1.

1Center for Transplantation Sciences, Massachusetts General Hospital, Boston, MA, United States; 2Department of Anesthesiology, University Hospital Hamburg-Eppendorf, Hamburg, Germany; 3eGenesis Inc., Cambridge, MA, United States

Introduction Previous studies showed that ischemia minimization (IM), accomplished by perfusing the heart xenograft during storage, prevents ‘initial cardiac xenograft dysfunction’ (ICXD) and enables prolonged survival following in vivo orthotopic cardiac xenotransplantation. Here we report initial observations in a model designed to evaluate effects associated with IM and genetic modifications on heart performance in a working ex vivo model of ICXD.

Method Hearts from genetically modified and wildtype (WT) pigs were procured after flushing with cold preservation solution (UW, 4°C) and stored for 3 hours either in cold saline (0.9%, 4°C: cold storage (CS)) or were perfused with oxygenated Steen’s solution with RBCs (IM). IM perfusion at 40 mmHg was initiated at room temperature for 20 minutes to facilitate homogeneous graft perfusion before cooling to 4°C for the remainder of the storage period. The genetically modified hearts either had combined knockouts of three specific xenogenic carbohydrate genes (GTKO, CMAHKO, b4GALNT2KO: TKO) with variable expression of human complement- and thrombo-regulatory genes (n=13); or GTKO with additional expression of hCD55 (GTKO.hCD55; n=2). Heart function and laboratory parameters were assessed at specific timepoints on a working heart rig while perfused with freshly collected heparinized whole human blood. Troponin I was used as a marker for myocardial injury. 

Results In total, 19 hearts were perfused ex vivo, ten with CS (TKO n=6, GTKO.hCD55 n=1, WT n=3), and 9 with IM (TKO n=7, GTKO.hCD55 n=1, WT n=1). Mean troponin I elaboration (ng/mL) was significantly reduced after 1 hour of ex vivo perfusion in the IM group (70.2 ng/mL vs. 279.5 ng/mL; p = .038), but not at final time points (see fig. 1a-c). Similarly, the cardiac function (measured in cardiac output (CO) in response to increased filling pressures) decreased over time after CS, whereas the IM-stored heart function remained relatively preserved (see fig. 2).

Conclusion IM significantly decreased myocardial injury during the first hour of ex vivo working heart perfusion relative to CS hearts: heart injury (troponin release) was attenuated, and graft failure was delayed in some TKO hearts treated with IM. Evaluation of whether variation in expression of human transgenes may have influenced TKO graft protection from IXD is in progress. We provisionally conclude that IM attenuates ICXD of genetically modified pig hearts during initial exposure to human blood. Whether IM is synergistic with effects associated with specific genetic modifications can be efficiently assessed in this model.

German Heart Foundation (Deutsche Herzstiftung e.V.).