Honoring 50 Years of Clinical Heart Transplantation in Circulation: In-Depth State-of-the-Art Review

Josef Stehlik, MD, MPH; Jon Kobashigawa, MD; Sharon A. Hunt, MD; Hermann Reichenspurner, MD, PhD; James K. Kirklin, MD


Circulation. 2018;137(1):71-87. 

In This Article

Current and Future Innovations in the Field of Heart Transplantation

The past 50 years of clinical transplantation have seen continued advances in the care of heart transplant recipients and a concomitant improvement in survival (Figure 4). The perfection of surgical techniques, modern immunosuppressive therapies, avoidance of a hostile immune environment for the allograft, and implementation of rigorous transplant care protocols have all contributed to better outcomes.[18] The key innovations being pursued in the field can be broadly classified as investigations aimed at increasing the availability of donor organs and approaches aimed at improving the long-term survival of patients after heart transplantation.

Ex Vivo Organ Perfusion

Ex vivo perfusion of donor hearts is being actively investigated as a means of increasing the number of organs suitable for transplantation. Rather than being stored in an arrested and hypothermic state, donor hearts are preserved in a warm, beating state. This approach has now been tested clinically in the PROCEEDII trial (Randomized Study of Organ Care System Cardiac for Preservation of Donated Hearts for Eventual Transplantation), in which the 30-day posttransplantation survival was similar with standard storage techniques and with ex vivo perfusion.[92] These favorable results open the opportunity to test ex vivo perfusion as a platform to assess or even improve the quality of organs in which questions about the suitability of the allograft are raised at the time of procurement. Furthermore, if it can be demonstrated that the organs can be perfused for extended periods of time without compromising the viability of the allograft, this could have major implications on how heart allografts could be allocated in the future in the absence of geographic restrictions related to acceptable transportation time.

Donation After Circulatory Death

Another approach likely to expand the current donor pool is heart transplantation using allografts from donation after circulatory death in which organs for transplantation are procured after circulatory cessation in severely ill but not brain-dead donors after the withdrawal of life-sustaining care. The first heart transplantations performed in the 1960s were technically donation after circulatory death transplantations, being done before establishment of brain-death criteria, but until recently, there has been very limited use of donation after circulatory death in heart transplantation,[93] related to both ethics considerations and the concern for injury to the allograft during donor hypotension after the withdrawal of life support. This obstacle is now being addressed through the technological advances in ex vivo perfusion. Investigator teams in Australia and the United Kingdom have reported successful clinical application of this approach.[21,94]

ABO-incompatible Heart Transplantation

ABO-incompatible heart transplantation has been introduced to clinical care by West et al.[95] ABO-incompatible heart transplantation usually results in hyperacute rejection caused by preformed recipient serum antibodies directed against blood-type antigens of the donor. However, infants do not produce these antibodies for the first [almost equal to]6 months of their life. The investigators implemented successful protocols for peritransplantation and posttransplantation care of infants undergoing ABO-incompatible heart transplantation. These protocols have now been adopted by multiple countries and have allowed expansion of the scarce donor pool for infants awaiting transplantation.

Immune modification to allow ABO-incompatible heart transplantation in older children and adults is currently underway.[96]


Xenotransplantation explores transplantation of organs between different species. Leonard Bailey at Loma Linda University performed the first cardiac xenotransplantation in 1984, transplanting a baboon's heart into an infant with hypoplastic left heart syndrome. The baby survived 12 days, dying of multiorgan failure but without evidence of rejection. In part as a result of public outcry against the use of primates, Bailey never performed another xenotransplantation.

In the past few decades, a small number of clinical kidney and liver transplantations using nonhuman primate grafts have been performed. The function of the transplanted organs has been limited to only days or weeks, a result of a powerful response of the human immune system against the nonhuman donor antigens, not overcome by the standard immunosuppression. However, the greatly improved genome-editing techniques that allow speedy genetic modification of antigen expression in animal models have resulted in renewed interest in xenotransplantation with a porcine model. Preformed circulating serum antibodies in humans that react with the swine leukocyte antigens, proteins of the major histocompatibility complex of the pig, used to represent a strong immune barrier. Recently, knockout pigs that lack major swine leukocyte antigen genes have been engineered, producing animals that do not express 3 key nonhuman swine leukocyte antigens. This reduced the immunogenicity of these organs in a human recipient.[97] Anti-HLA antibodies may still cross-react with other antigens expressed on the porcine cells, but additional genetic modification may soon diminish this problem.

In a heterotopic heart transplantation model, knockout pig to nonhuman primate allograft survival of up to 945 days has been demonstrated. This required higher-than-standard immunosuppression, including maintenance with anti-CD40 antibody. Disappointingly, survival of orthotopic pig to nonhuman primate heart transplantation grafts has so far been limited to <2 months, mostly as a result of perioperative cardiac xenograft dysfunction, which is believed to be distinct from acute rejection.[98]

Another concern in xenotransplantation is the risk of infection transmission. Maintenance of donor animals in pathogen-free facilities may reduce the risk of bacterial, fungal, and exogenous viral infection. All pigs also carry endogenous retroviruses, yet so far, there has been no documentation of transmission of the retroviral genetic material from pigs to nonhuman primates through xenotransplantation.[99]

Although a number of biological and logistical issues remain to be resolved before pig to human heart transplantation can be undertaken, recent calls for clinical testing of pig to human kidney transplant provide a reason for optimism.

Organ Engineering

The immune and infectious challenges faced by xenotransplantation could be circumvented by organ engineering. The proof of concept of this approach was demonstrated by Ott et al.[100] These investigators first generated decellularized extracellular matrix scaffolds of rat hearts by removing cellular tissue from the organs. These scaffolds then provided biomechanical and topographical support for autologous neonatal cardiac cells that repopulated this scaffold.[100] The recellularized hearts showed some automatic contractility and responded to medications. Before this approach can come closer to the clinic, a number of obstacles that would translate this model to a functional bioartificial organ need to be resolved.

Immune Tolerance

In addition to finding new sources of donor organs, improvement of long-term survival remains a priority in heart transplantation. Key improvements in posttransplantation survival in the past decades have been limited predominantly to the first posttransplantation year.[18] However, long-term survival past the first year after transplantation, while markedly better compared with medical treatment of stage D heart failure, is still lower compared with a healthy population. Historically, there have been high expectations that long-term survival will be improved by new immunosuppressive medications, anticipated to provide adequate levels of immunosuppression and a more favorable side-effect profile. Nevertheless, none of the immunosuppressive regimens introduced after CNIs and MMF have been shown to reduce mortality in heart transplantation.

An alternative approach to refining the effect of immunosuppressive therapies would be to reduce the need for immunosuppression through the induction of tolerance of the recipient's immune system to the donor antigens. The main approaches that have shown potential of inducing immune tolerance have been T-cell costimulation blockade (prevention of T-cell activation by donor antigens), mixed-chimerism strategies (recipient bone marrow engraftment with donor bone marrow cells), transient profound T-cell depletion (elimination of recipient T cells at the time of transplantation), and regulatory T-cell approaches (infusion of expanded donor regulatory T cells).[101] Although many of these approaches have induced tolerance in small animal models, translation of these findings to humans has so far not been successful.

Molecular Diagnostic Methods

In the absence of marked qualitative advances in immunosuppressive pharmacotherapy or clinically applicable induction of immune tolerance, it is possible that there are reserves in personalization of the current treatments to individual patients. A recent report by Wever-Pinzon et al[102] highlighted this issue through examination of the leading causes of death in 52 995 heart transplant recipients. The authors showed that there was a strong relationship between the age at transplantation and the hazard of cause-specific death. Patients transplanted at a younger age were several times more likely to die of acute rejection, CAV, and nonspecific graft failure, whereas recipients transplanted at an older age were more likely to die of malignancy and infection. These data suggest that younger patients may be relatively underimmunosuppressed and older patients are more likely to suffer the consequences of overimmunosuppression. Indeed, most protocols tailor the level of immunosuppression to time since transplantation. However, truly individualized adjustment of the level of immunosuppression based on the risk of rejection and risk of immunosuppression-related adverse events is challenging to implement. It has been proposed that this level of personalization may be possible with molecular diagnostic techniques. Gene-expression profiles of rejection-related genes in peripheral white blood cells (Allomap test described earlier), both as individual values and in the assessment of their stability over time, have been shown to provide prognostic information related to clinical events.[33,103] Similarly, gene-expression profiles in myocardial tissue have been shown to segregate into distinct archetypes correlated with the probability of acute cellular rejection, AMR, and nonrejection.[35,104] Although the current use of this information is related mainly to decisions about the treatment of acute rejection, these tests could in the future provide a platform for individualized adjustment of the level of maintenance immunosuppression.

Once innovation in the MCS space generates devices requiring less intensive patient and caregiver involvement coupled with better long-term survival, new questions will arise about how to best combine durable MCS with heart transplantation to optimize patient survival and quality of life in the long term. Thus, approaches that will include intermediate- to long-term use of MCS followed by heart transplantation or, alternatively, heart transplantation followed by MCS once the functional graft lifetime is exhausted will undoubtedly be examined.