Cardiac xenotransplantation: from concept to clinic

Abstract

For many patients with terminal/advanced cardiac failure, heart transplantation is the most effective, durable treatment option, and offers the best prospects for a high quality of life. The number of potentially life-saving donated human organs is far fewer than the population who could benefit from a new heart, resulting in increasing numbers of patients awaiting replacement of their failing heart, high waitlist mortality, and frequent reliance on interim mechanical support for many of those deemed among the best candidates but who are deteriorating as they wait. Currently, mechanical assist devices supporting left ventricular or biventricular heart function are the only alternative to heart transplant that is in clinical use. Unfortunately, the complication rate with mechanical assistance remains high despite advances in device design and patient selection and management, and the quality of life of the patients even with good outcomes is only moderately improved. Cardiac xenotransplantation from genetically multi-modified (GM) organ-source pigs is an emerging new option as demonstrated by consistent long-term success of heterotopic (non-life-supporting) abdominal and life-supporting orthotopic porcine heart transplantation in baboons, and by a recent ‘compassionate use’ transplant of the heart from a GM pig with 10 modifications into a terminally ill patient who survived for two months. In this review, we discuss pig heart xenotransplantation as a concept, including pathobiological aspects related to immune rejection, coagulation dysregulation, and detrimental overgrowth of the heart, as well as GM strategies in pigs to prevent or minimize these problems. Relevant results of heterotopic and orthotopic heart transplantation experiments in the pig-to-baboon model, microbiological and virologic safety concepts, and efficacy requirements for initiating formal clinical trials are additional topics discussed. An adequate regulatory and ethical framework as well as stringent criteria for the selection of patients will be critical for the safe clinical development of cardiac xenotransplantation, which we expect will be clinically tested during the next few years.

Hemodynamics in pig‐to‐baboon heterotopic thoracic cardiac xenotransplantation: Recovery from perioperative cardiac xenograft dysfunction and impairment by cardiac overgrowth

“…Our findings support the thesis that the heterotopic model could be a possible method to overcome PCXD (or other forms of xenograft failure) in early clinical trials 14,17 . In our current study, PCXD was reversible with the support of hearts from healthy baboons.…”

“…Similar to preclinical orthotopic cardiac xenotransplantation experiments, the ubiquitous growth hormone inhibitor rapamycin may be given 2,7 . Ideally, organs from smaller donor animals would also be used in the heterotopic thoracic setting such as pigs with growth hormone receptor deficiency 12,13 or Auckland Island pigs 17 …”

“…The xenograft is connected to the recipient's heart, which is left in situ. So, the xenograft can partly or fully support the recipient's organ perfusion requirements 17–19 . Although the heterotopic technique is a clinically accepted method in human allotransplantation, 19–22 only the orthotopic procedure is currently performed, in part because of the complexity of the heterotopic procedure.…”

Current Status of Cardiac Xenotransplantation: Report of a Workshop of the German Heart Transplant Centers, Martinsried, March 3, 2023

“…In 2000, the Xenotransplantation Advisory Committee of the International Society for Heart and Lung Transplantation recommended that consistent survival of non-human primates supported by orthotopic porcine heart transplants for 3 months would be sufficient to warrant a clinical trial 87 . However, advancements in the field have raised the bar for evidence, with some suggesting that consistent survival of up to 6 months without irreversible rejection or infection would be more appropriate for initiating clinical trials in carefully selected patients 7,10,88 . Extending survival durations to nine or even 12 months with one or two recipients would provide further assurance.…”

“…In 2000, the Advisory Committee of the International Society of Heart and Lung Transplantation set up criteria, when the first clinical trial should be considered 87 . The required preclinical results have been met: consistent survival of two third of the life-supporting porcine heart replacements in non-human primates, in good health for up to a minimum of 3 months (has recently been extended for 6 months, or in single cases longer 7,8,10,88 .…”