Heart to Heart: Could Pig-to-Human Heart Transplants Become a Reality?

Heart failure is a syndrome in which the heart has become too weak or stiff to adequately pump blood around the body. This can significantly impact the quality of life of those affected, with breathlessness, fatigue, and fainting being some of the most prominent symptoms. In the U.S., around one in four people will develop heart failure over the course of their lives (Bozkurt et al. 2023).

Currently, the gold-standard treatment for advanced heart failure is heart transplantation (Chun and Kang 2023). However, the supply of suitable donors for this procedure is limited. According to the Health Resources and Services Administration (HRSA), there were 3,436 people on the waiting list for heart transplantation as of March 2024, and 17 people on organ transplant lists die each day waiting for suitable tissue to become available.

But what if help could be found in an unlikely ally?

The Heart of a Pig

Believe it or not, many scientists believe that pigs may come to our rescue in this challenge. With similar organ size and shape to humans, pigs are often considered to be the best source for animal-to-human transplantation (also known as xenotransplantation) (Wang et al. 2022).

However, there are still problems with using pigs as donors that need to be understood and overcome for the full potential of xenotransplantation to be unlocked. One of the most critical challenges is graft rejection. This is mediated by the strong immune response of the recipient elicited following the appearance of foreign tissue in the host body. One study performed in the 1980s showed that when nonhuman primates received organs from wildtype pigs, rejection occurred within minutes or hours due to antibody-dependent complement-mediated tissue injury (Lexer et al. 1986). Additional issues associated with the use of porcine donor organs include the excessive growth of the organ in the recipient and potential problems associated with blood coagulation (Singh et al. 2019).

Fortunately, another key benefit of using pigs as organ donors is the ability to edit their genomes (Wang et al. 2022). So, where has this capability to genetically alter the hearts of pigs gotten us so far?

A Change of Heart

Remarkably, two groundbreaking pig-to-human heart transplants have recently been performed with genetically altered donor animals.

The genomes of the pigs had been engineered with ten strategic changes. Three of these edits were to knock out the genes that encode the major glycan xenoantigens typically expressed on the cell surface of pig cells. These antigens, galactose-α1,3-galactose (αGal), N-glycolylneuramine acid (Neu5Gc), and Sia-α2.3-[GalNAc-β1.4]Gal-β1.4-GlcNAc (Sd(a)), are suspected to be the main culprits behind rejection by preformed antibodies in the host so they were a prime target for manipulation.

 An additional tactic to reduce the risk of rejection was implemented; human transgenes were incorporated into the pig genome, enabling the production of human complement factors, CD46 and CD55, and anti-inflammatory proteins, CD47 and heme-oxygenase 1 (HO-1). This can essentially trick the host immune system into not recognizing the presence of foreign tissue and preventing the activation of complement-mediated graft injury.

Lastly, human thrombomodulin and endothelial cell protein C receptor (EPCR) were expressed to overcome issues with dysregulated coagulation, and the growth hormone receptor was deleted to halt the growth of the xenograft (Griffith et al. 2022). Overall, these changes were hoped to overcome many of the common pitfalls associated with xenotransplantation.

The Outcome

With the designer pigs in hand, surgeons at the University of Maryland School of Medicine recruited a 57 year old man named David Bennett, hospitalized for severe heart failure, to be the first living human in history to receive this revolutionary surgery. After previous treatment attempts failed, Bennett had suffered multiple cardiac arrests necessitating resuscitation and dependence on extracorporeal membrane oxygenation (ECMO), a type of life support providing cardiac and respiratory aid. Unfortunately, Bennett was not eligible for conventional human organ transplantation and thus decided to undergo xenotransplantation.

Following the surgery, the patient‘s T and B cells were depleted to prevent rejection of the xenograft, and KPL-404, a monoclonal antibody that inhibits CD40 interactions and subsequent T cell costimulation, was initiated as an immunosuppression maintenance regime.

Amazingly, the graft was able to support Bennett for around seven weeks without ECMO support. After being bedbound for 109 days, Bennett was able to sit, unaided, in a chair on day 48 post transplantation. Unfortunately, not long after this, his condition began to decline, and he was put back on life support. On day 60, Bennett’s condition was deemed irreversible, and life support was compassionately withdrawn (Griffith et al. 2022).

The reasons for the xenograft failure have been studied since and it has been hypothesized that the administration of intravenous immunoglobulin G, given in an attempt to counteract the patient’s low blood immunoglobulin levels, likely contained anti-pig antibodies and may have triggered antibody-mediated rejection. Furthermore, latent porcine cytomegalovirus was found in the pig heart, which may have reactivated in its new human environment (Mohiuddin et al. 2023).

The second patient to receive this novel treatment option was a man called Lawrence Faucette, who also suffered from heart failure and was unsuitable for conventional transplantation due to his preexisting peripheral vascular disease and issues with internal bleeding. While less is known about the details of Faucette’s case as it has yet to be published in the literature, it is known that he survived for around 6 weeks with the xenoheart before unfortunately succumbing to his condition. It’s been hypothesized that rejection was the cause of death in this case (Cooper and Cozzi 2024). 

While neither patient survived for more than around two months, this is a critical step in xenotransplantation history. Knowing the cause of death of these two patients will allow scientists to develop innovative strategies to overcome the problems experienced so far. Furthermore, it has been proposed that xenotransplantation could be used as a bridging therapy, to maintain the health of the patient until a suitable human organ becomes available (Cooper and Cozzi 2024).

Overall, a lot more research is needed before this potential therapeutic option can become a part of mainstream medicine. However, the results so far are promising. So, don’t lose heart! Pigs could still save our bacon after all.