Xenogeneic orthotopic heart transplantation: Where are we now?

Abstract

Cardiac xenotransplantation is a promising option for satisfying the unmet need for cardiac replacement. Mechanical hearts have been in development for over 40 years and only one device is currently available “off the shelf” for implantation in the United States. It took 39 years for this first approved device to be available. This device approval arose from outcomes from the rematch trial (2001) when survival in the ventricular assist device group was fifty‐two percent and twenty‐three percent at 1 and 2 years, compared with twenty‐five percent and eight percent in the medically treated group. Quality of life was significantly improved at 1 year in the ventricular assist device group. While mechanical support continues to improve, intrinsic disadvantages remain, such as thromboembolism, the need for careful anticoagulation, infection, lack of physiological response, durability and power supply. Pursuit of cardiac xenotransplantation therefore remains a potentially important contributor to the treatment of heart failure clinically.With the addition of human complement regulating proteins to the pig genome using a micro‐injection technique and the subsequent development of Gal knockout pigs using cloning technology, pre‐clinical median survival of heterotopic cardiac xenotransplants is now in excess of 3 months. A three months median survival of orthotopic cardiac xenotransplants has been proposed as a possible threshold for a clinical trial. Attention has therefore focused on the orthotopic cardiac xenotransplant pig to baboon model. There have been six operative survivors ranging from 2 to 57 days. Immunosuppression in these recipients consisted of ATG induction, tacrolimus, sirolimus, anti‐CD20 and a steroid taper. No anticoagulation was used. None of the animals died of rejection. The causes of failure largely related to the challenges of the model system. In four of the six cases rejection was minimal and the remaining two mild to moderate. Recipients were healthy and well during the post‐operative period. Biochemistry was stable. Challenges encountered during these studies have included early peri‐operative heart failure which has markedly improved with peri‐operative management. These studies have shown maintenance of normal cardiac function for up to 2 months following pig to baboon transplantation. In addition, hearts from the recipients who survived showed peri‐operative myocardial dysfunction that completely recovered post‐operatively within a few days.Outcomes of pre‐clinical orthotopic cardiac xenotransplantation continue to improve with this report describing the longest survivors to date. Porcine hearts can function normally in primates for at least 2 months. Peri‐operative cardiac dysfunction is likely avoidable and is recoverable. Reparative processes are intact in the xenotransplant setting. Cardiac xenograft rejection is well controlled on tolerable immunosuppressants. Model limitations remain a serious challenge. The powerful advantage of biologic cardiac replacement (complete implantability, intrinsic power supply, lack of need for anticoagulation and physiological responsiveness) justifies continued pre‐clinical studies. In the first instance the goal of clinical cardiac xenotransplantation will be to provide additional treatment alternatives for patients with end‐stage organ failure. The comparison on outcomes will be with other available treatments and not allotransplantation in the first instance.Research programme supported by NIH Grant A166310.