Surgical and Nonsurgical Complications of a Pig to Baboon Heterotopic Heart Transplantation Model

Abstract

A modified immunosuppressive regimen, developed at the National Institutes of Health, has been employed in a large animal model of heterotopic cardiac xenotransplantation. Graft survival has been prolonged, but despite this, our recipients have succumbed to various surgical or nonsurgical complications. Herein, we have described different complications and management strategies. The most common complication was hyperco-agulability (HC) after transplantation, causing thrombosis of both small and large vasculature, ultimately leading to graft loss. While managing this complication we discovered that there was a delicate balance between HC and consumptive coagulopathy (CC). CC encountered in some recipient baboons was not able to be reversed by stopping anticoagulation and administering multiple blood transfusions.Some complications had iatrogenic components. To monitor the animals, a solid state left ventricular telemetry probe was placed directly into the transplanted heart via the apex. Induction of hypocoagulable states by continuous heparin infusion led to uncontrollable intra-abdominal bleeding in 1 baboon from this apical site. This occurrence necessitated securing the probe more tightly with multiple purse strings and 4-quadrant pledgeted stay sutures. One instance of cardiac rupture originated from a lateral wall infarction site. Earlier studies have shown infections to be uniformly fatal in this transplant model. However, owing to the telemetry placement, infections were identified early by temperature spikes that were treated promptly with antibiotics.We had several cases of wound dehiscence due to recipients picking at the sutures. These complications were promptly resolved by either re-approximating the wound or finding distractions for the baboon. A few of the most common problems we faced in our earlier experiments were related to the jacket, tether, and infusion pumps. It was difficult to keep the jackets on some baboons and the tether had to be modified several times before we assured longterm success. Infusion catheter replacement resulted in transplant heart venous obstruction and thrombosis from a right common femoral venous line. Homeostatic perturbations such as HC and CC and baboon-induced wound complications comprised most complications. Major bleeding and death due to telemetry implantation and infarct rupture occurred in 2 baboons. Despite the variety of complications, we achieved significant graft prolongation in this model.

Role of anti‐CD40 antibody‐mediated costimulation blockade on non‐Gal antibody production and heterotopic cardiac xenograft survival in a GTKO.hCD46Tg pig‐to‐baboon model

“…We have previously shown that by depleting B cells with anti-CD20 antibody, costimulation blockade by anti-CD154 antibody, and treatment with MMF, we can prolong cardiac xenograft survival in a pig-to-baboon model for up to 236 days [4]. Despite achieving significant graft prolongation in the above group of experiments, we encountered several complications leading to recipient death or need for euthanasia before the transplanted heart fully rejected [31]. In our experience and also by others, anti-CD154 antibody use resulted in complications including TM, CC, and bleeding [8,32].…”

Genetically engineered pigs and target-specific immunomodulation provide significant graft survival and hope for clinical cardiac xenotransplantation

“…Some other complications experienced over the length of the project included abdominal bleeding. GI bleeding, aspiration pneumonia, seizures, thrombocytopenia and anemia (21). …”

Cell Size and Velocity of Injection are Major Determinants of the Safety of Intracarotid Stem Cell Transplantation

“…This prompted us to study the risks of intracarotid cell transplantation and determine which factors are most relevant for developing safe injection protocols. Microvascular thrombosis is a major complication of solid organ xenografts 13,14 and, thus, we first hypothesized that the presence of xenogeneic cells in cerebral vessels may be a factor contributing to the thrombosis and subsequent strokes that we observed in our hGRP grafts. As human-to-rat is a discordant xenotransplantation, it activates the immune system more profoundly than concordant xenografts.…”