Innovative strategies to increase cardiac donor availability

Abstract

Heart transplantation is a life-saving procedure for many people throughout the world. Data shows that in 2024, there was an increase in the volume of adult heart transplantation in the United States even as there was a decrease in the volume of pediatric heart transplantation to the lowest volume in a decade. Organ availability remains a major limiting factor affecting transplant volume. This mandates that innovation must take place to increase the supply of donor organs. While some strategies such as donation after cardiac death, hepatitis C virus + transplantation, and ABO-incompatible transplantation have increased the pool for donation, it still falls short of meeting the demand. Other proposed strategies include splitting the donor heart to provide multiple partial heart transplants, domino partial heart transplantation, changes in legislation including opt-out legislation, and xenotransplantation. Further evolution and refinement of these strategies will make a meaningful impact on patients awaiting life-saving heart transplants.

Key Words: Heart transplantation; Partial heart translation; Domino transplantation; Organ availability; Valvular transplantation

Core Tip: Heart transplantation is a procedure for extending the life of patients subject to heart failure but is limited in capacity by the availability of organ donations. Here we present a review on surgical, medical and policy innovations that can be used to increase the availability of donor organs for the general public.

INTRODUCTION

It is estimated that 6.7 million Americans over the age of 20 suffer from heart failure accompanied by an estimated 603000 annual deaths due to any cause of heart failure[1]. In pediatric patients it is estimated that hospitalizations related to heart failure occur in up to 14000 children annually with an approximated mortality of 7% in the United States[2]. The primary underlying causes for heart failure worldwide was found to be ischemic heart disease (26.5%), hypertensive heart disease (26.2%), chronic obstructive pulmonary disease (23.4%), other cardiomyopathies (6.5%), non-rheumatic degenerative mitral valve disease (2.7%), other cardiovascular and circulatory disease (2.4%), alcoholic cardiomyopathy (2.4%), non-rheumatic calcific aortic valve disease (2.3%), rheumatic heart disease (1.8%) and myocarditis (1.7%) (Table 1)[3]. In 2016, it was found that there were 7932 emergency department visits and 12249 hospitalizations for pediatric patients with heart failure. The most common comorbidities in pediatric patients with heart failure was congenital heart disease (46.6%), arrhythmias (14.7%), cardiomyopathy (12.4%), hypertension (12.2%), and acute kidney failure/chronic kidney disease (11.4%) (Table 1)[4]. The first orthotopic heart transplant was performed in 1967 and has since then become the gold standard for patients with advanced or end-stage heart failure. Heart transplant outcomes have dramatically improved over the decades. In the early years, from 1967 to 1973, patient survival rates were dismally low at just 30%. A significant breakthrough came with the introduction of cyclosporine and other immunosuppressive medications, which boosted survival rates to 60% between 1974 and 1980. This marked a crucial turning point in transplant medicine. In the contemporary era, further advancements in medical technology and patient care have pushed early survival rates to impressive heights, now hovering around 90%[5]. The median survival for heart transplant recipients between 2002 and 2009 was found to be 12.5 years, extending to 14.8 years for patients that survive the first initial year[6]. 2024 Organ Procurement and Transplantation Network (OPTN) data states that 4074 and 486 heart transplants were completed in adult and pediatric patients respectively in the United States (Table 1).

Table 1 Indications of heart transplant in adult and pediatric populations.

Diseases	Indication
Adults
Ischemic heart disease	26.50%
Hypertensive heart disease	26.20%
Chronic obstructive pulmonary disease	23.40%
Other cardiomyopathy	6.50%
Non-rheumatic degenerative mitral valve disease	2.70%
Alcoholic cardiomyopathy	2.40%
Non-rheumatic calcific aortic valve disease	2.30%
Rheumatic heart disease	1.80%
Myocarditis	1.70%
Children
Congenital heart disease	46.60%
Arrythmias	14.70%
Cardiomyopathy	12.40%
Hypertension	12.20%
Acute kidney failure/chronic kidney disease	11.40%

Orthotopic heart transplantation is considered the treatment of choice for patients with heart failure, but it has long been plagued by the immense shortage of available donor allografts, limiting its therapeutic capacity to only a percentage of patients each year on waitlists[7]. In 2022 there were 4446 new adult and 703 new pediatric candidates registered to receive heart transplants. Analysis of cardiac transplant rates found that adult heart transplant rates (122.5 transplants per 100-patient years) have continued to increase, but pediatric heart transplant rates have decreased to their lowest in the past decade (104.2 transplants per 100-patient years). In adult patients with valvular heart disease, pre-transplant mortality increased 50.1% from 8.77 deaths in 2011 to 13.2 deaths per 100 patient-years in 2022[8]. Based on 2024 OPTN data, 3041 adult patients and 534 pediatric patients remain on the heart transplant list. Waitlist mortality amongst adults and pediatric patients continues to fall but remains excessively high for infant patients under one year of age at a staggering 25.7 deaths per 100 patient-years[8]. Domino partial heart transplantation (PHT) was first performed in 2024, but there is limited published data on success rates and potential surgical challenges. This novel approach awaits further research and clinical experience to establish its efficacy and identify any specific complications associated with the procedure. It was found that between 2017 and 2021, the average number of discarded donor hearts was 38% (78) in neonate/infant, 49.4% (41) in toddler, 49.4% (41) in young child, 38.0% (240) in adolescents (10-18 years) and 40.1% (498) in young adults. The most common reasons found for discard/non-allocation were heart valve industry distribution (26.5%), suboptimal organ function (22.7%), and logistical challenges (10.8%)[9]. The logistical challenges primarily revolve around the fact that conventional heart transplants require procurement teams to limit cold ischemic times to under six hours. This limits the organ availability for patients in need of transplants, especially to patients located in lower population areas. The discrepancy observed between transplant numbers compared to those actively awaiting an organ donor highlights the severity of the decreased donation capacity.

Certain measures have already been put into place in order to increase the availability of cardiac donor organs including the usage of extended criteria donors and donors with hepatitis C, but this still fall short of meeting organ demand[10,11]. In an attempt to address the ongoing need for increased availability of cardiac donor tissue and organs, many scientific innovations and policy changes have been proposed as ways to bridge the gap between supply and demand for the treatment of patients with heart failure. The purpose of this article is not to give a full review of each innovation discussed, but rather to briefly illustrate innovations occurring in the ever-evolving world of cardiac transplantation and how they can increase the donor organ supply pool to make possible life-changing care for patients with heart failure (Figure 1)[9].

Figure 1 Strategies to expand cardiac donor availability.

PHT

As a potential way to increase the availability of donor tissue to the cardiac donor pool, cardiothoracic researchers are beginning to utilize PHT as an alternative to cadaver homograft valve replacements. PHT allows the native ventricles to be spared by only transplanting the portion of the heart encompassing the outflow valves[12]. PHT is a novel surgical technique in the field of pediatric cardiothoracic surgery and was first implemented in 2022. The index case consisted of a neonate with truncus arteriosus and severe truncal valve dysfunction who received both a pulmonary and aortic valve from a two-day-old female that had suffered hypoxic brain injury during delivery. At one year post-operation, the PHT recipient showed growth of both the neo-aortic and neo-pulmonic valves without insufficiency or obstruction[13]. PHT makes possible the split-root technique which can be used to maximize a single donor heart, deemed non-viable for conventional transplantation, for two pediatric recipients. This innovative surgical technique could effectively double the availability of pediatric semilunar valves and has the potential to solve the problem of neonatal valve replacement, for which there are currently only limited surgical options[12].

Children who require outflow valve surgery have historically been prone to poor surgical outcomes and high rates of reoperation because preserved homografts cannot grow or self-repair as the patient ages[13]. This is evident by the increased susceptibility to calcification, wear and tear, and endocarditis, which in turn sometimes requires neonate homograft recipients to receive additional reoperation for homograft replacement within months of the initial operation. Additionally, high rates of reoperation drive pediatric patients to poor outcomes, illustrated by a 28% and 40% in-hospital mortality in infants receiving any form of aortic valve replacement and patients undergoing homograft aortic valve replacement respectively[14]. The success of PHT in the clinical setting highlights the ability to provide pediatric patients with valves that continue to grow as they age. It is estimated that 43.3% of pediatric and young-adult heart valves were underutilized, with an estimated 900 valves discarded annually[9]. Additional studies have found that approximately 29, 39 and 230 recoverable valves from infants, toddlers and children respectively could be procured in the setting of PHT and potentially fulfill the organ requirements needed for patients with irreparable valvar dysfunction[15].

While PHT shows promise as an alternative to the current standard of care that we possess today, many unanswered questions remain. One area of focus that needs to be clarified is the need for immunosuppression in PHT recipients. Previous studies have noted that allograft heart valves have long-term functionality without human leukocyte antigens (HLA) or ABO matching and without immunosuppression[16]. This has been highlighted in studies showing that hearts transplants that have failed due to rejection still have functionally intact semilunar valves[17]. Further studies are needed to determine immunosuppression protocols to achieve valve growth in individuals who have received PHT. Additionally, PHT involves the use of allogenic tissue which places recipients at risk for sensitization. This could negatively impact their ability to match for future transplants[18,19]. Furthermore, due to the novelty of this surgical technique, long-term follow-up and larger patient cohorts are lacking. As research progresses, future studies and long-term data collection will be necessary to substantiate the hypothesis that PHT offers patients better outcomes and reduced reoperation rates when compared to conventional homograft valve replacement. Moreover, at the time this paper has been written, no partial heart transplants have been completed in the adult population or with valves other than the aortic and pulmonic valves[19].

DOMINO TRANSPLANTATION

The domino procedure is a surgical technique employed in the setting of multiple-organ transplant, that utilizes a viable explant from the transplant recipient that is subsequently utilized in another suitable patient[20]. The domino technique was pioneered by Yacoub et al[21] in 1988, when they first described the success of a domino heart-lung transplantation (HLT) for a patient with cystic fibrosis. Domino procedures have since evolved into more complex procedures evidenced by the success of domino liver transplantation, heart-liver domino transplantation, and domino PHT[22,23]. Domino PHT differs from traditional PHT by utilizing only the functional valves of orthotopic heart transplant recipients with viable semilunar valves[12]. Similarly to non-domino PHT, this is attempted simultaneously to maintain the viability of the autografted outflow tract valves[19,24]. Just like with the split-root technique for PHT, domino PHT can become a feasible strategy to expansion of the donor pool and reduce both waitlist time and mortality in pediatric populations, but future analysis is needed to assess the potential benefits and risks of this of the complex surgical technique[19].

Similar to that of the standard partial heart, patients are subject to the same risks associated with immunosuppression and sensitization that follow allogenic transplantation. As domino PHT was first performed in 2024, there is currently a lack of published data on success rates and potential surgical challenges. Further research and clinical experience is needed to establish its efficacy and identify any specific complications associated with the procedure and long-term risks and outcomes. Furthermore, domino PHT has only been completed with semilunar valves and has not been attempted in adult patients with heart failure.

ABO INCOMPATIBLE DONATIONS

ABO incompatible heart transplants (ABOi) are being heralded as a possibility to increase the cardiac donor pool, particularly children. Traditionally, ABO compatibility between the cardiac organ donor and recipient is required, and that ABO incompatibility can precipitate hyperacute or acute antibody mediated rejection[25]. ABO antigens are polysaccharide arrangements and differ from other immune structures. They are classified as T-cell independent type 2 antigens and instead activate B-lymphocytes. This discovery stemmed from multiple studies analyzing the increased frequency and severity that children under 5 face when infected with polysaccharide-encapsulated bacteria[26]. Additionally, it was found that infants and young children fail to produce an adequate response to polysaccharide vaccines compared to their adult counterpart[27]. Further studies found that human isoantibodies to blood groups A and B are elicited by intestinal bacteria and are typically absent in the first six months of life, gradually increasing to adult levels by the second year of life[28,29]. This led investigators to utilize this period of reduced immune surveillance to transplant ABOi organs into children under the age of two. In turn, serving as a potential mechanism to increase the donor availability of cardiac organs for pediatric patients desperately awaiting transplant[30]. OPTN’s current policy states that pediatric heart transplant candidates who are registered as status 1a or 1b before they turn two years of age are eligible for the option to accept hearts from ABOi donors.

The first analysis of ABOi heart transplants in children was completed by West et al[31] in 2006. They found that transplantation of ABOi donor hearts into young recipients significantly improves the chances of transplantation and reduces waitlist mortality. Additionally, they found that their model of time-related freedom from death or re-transplantation demonstrated no significant difference at four years post-transplantation for ABO incompatible patients (74%) vs ABO compatible patients (72%)[31]. A secondary study looking at ABOi and ABO compatible transplants completed by Dipchand et al[32] found similar results. Their analysis highlighted that ABOi patients and ABO compatible patients shared an identical seven-year survival of 74%. The first multicenter analysis of ABOi transplantation found similar results as well. Freedom from death or re-transplantation was 100%/96%/69% at 1/5/10 years post transplantation[33].

The success seen in ABOi transplantation is one of many ways to drastically increase the donor availability in our pediatric population. The standard ABO practice for organ allocation is based on adult populations with mature immune systems and limits ABOi organs to vulnerable pediatric populations. As a result, young patients are unnecessarily exposed to increased waitlist times and waitlist mortalities[33].

DONATION AFTER CARDIAC DEATH

The rise of potentially eligible heart transplant recipients and the stagnation in the number of heart organ donors, has led to a re-evaluation of donation after cardiac death (DCD) as a potential way to bridge the critical deficit of suitable donor organs[34]. DCD transpires when patients with devastating brain injury who have not progressed to neurological death but have exhausted treatment options are withdrawn from care and become organ donors[35]. DCD is further separated into two distinct categories. Controlled DCD occurs when a patient who has experienced a brain insult but has not progressed to electrosilence, is brought to the operating room for elective organ removal and procurement. Alternatively, an uncontrolled DCD occurs when a patient suffers unexpected cardiac arrest outside the operating room[36]. In 2019, DCD organs represented 23% of all kidney, liver, pancreas and lung transplantations in the United States. Due to the ethical and technical constraints that exist in the United States in regards to DCD heart transplantations, little data is available for analysis of clinical outcomes and evaluation of the best techniques for DCD donor heart recovery[37].

A retrospective study headed by the Smidt Heart Institute at Cedars Sinai Medical Center found that heart transplantation after DCD has comparable short-term survival to heart transplantation following donation after brain death (DBD). Six-month survival was 92.1% following DBD heart transplants and 92.6% following donation after circulatory death heart transplants[38]. These results were reinforced by a study published by New York University which found that a combination of donor resuscitation, decrease in warm and cold ischemic time led to excellent DCD results, comparable to those of DBD. Furthermore, a randomized, noninferiority trial compared the safety and efficacy of the transplantation of hearts from donors after DCD compared with those obtained from donors after DBD. This trial found that the risk-adjusted six-month survival after transplantation of a donor heart that had been resuscitated and assessed with the use of extracorporeal nonischemic perfusion after circulatory death was not inferior to the standard of care transplantation with the use of cold storage following brain death[39].

Donation after circulatory death is a controversial topic of debate. While the data and results of DCD supports its application to a wider net of patients, it could face moral and social backlash both from the public which can hinder its adoption into standard medical care. In order for it to gain acceptance, it will need to be subject to stringent policy. The decision to withdraw life supportive treatment should be completely independent of the transplant team and no conflict of interest should exist or be perceived to exist. Religious beliefs may impact implementation of DCD[40].

Although heart transplantation following DCD is not universally adapted yet, the available results showcase favorable outcomes for its recipients and the potential to drastically increase the availability of viable donor heart allografts in the United States for patients with heart failure[41,42].

PRESUMED CONSENT

Another way that researchers have proposed to increase donor organs is from a policy standpoint. Presumed consent or an “opt-out” policy states that all individuals are deemed organ donors unless they explicitly opt-out[43]. This principle again is subject to ethical controversy, but recent studies have found no difference in organ donation rates between countries that practice opt-out organ donation vs opt-in countries. The importance of first addressing the personal, familial, religious, and cultural barriers to organ donation cannot be overstated prior to implementation of any regional or national policies of presumed consent[44].

In 2008, Spain established the 40 Donors per population million (pmp) Plan to consider novel strategies to meet their increasing demand for organ transplantation and to ensure that the option of organ donation is given to patients and their families at the time of death[45]. While Spain is a country that operates on an opt-out basis, the success of their donation rate is not just a result of their legislation[46]. Their plan consisted of promoting early identification and referral of potential organ donors to consider non-therapeutic care, including the option of organ donation into palliative care; expanding upon the ability to donate by using expanded and non-standard risk donors; and development of a framework for DCD. The success of the 40 donors pmp Plan is evident by Spain’s continued increase from 34 deceased donors pmp in 2008, to 40 donors pmp in 2015. This is now being modeled by other countries and regions to increase the limited quantity of viable organ donors[47].

In theory, opt-out legislation provides additional organs to become readily available to the donor pool. This assumption is backed by the idea that underwhelming organ donation rates are due to poor societal contribution and a negative attitude toward donation, rather than barriers that exist within our healthcare infrastructure[48].

XENOTRANSPLANTATION

Cardiac xenotransplantation from genetically multi-modified pigs is another potential emerging innovation to address the increased need for both pediatric and adult organs necessary for cardiac transplantation[49]. Porcine hearts have been chosen as a potential donor species due to their similar size and anatomy to human hearts, the ability for genetic modification, advantageous breeding conditions, and their relatively low risk for infection[50].

Cardiac xenotransplantation is subject to a variety of complex challenges that have limited the success of pig-to-human transplantation. The main immunological barrier for successful xenotransplantation is the presence of natural anti-pig antibodies in humans and nonhuman primates that bind to antigens, most commonly galactose-a1,3-galactose located on the pig organ xenograft. This cascade in turn activates the compliment cascade leading to hyperacute rejection of the porcine xenograft[5,51]. This has led to the development of genetically engineered pigs that are deficient in the galactose antigen, significantly reducing the risk of hyperacute transplant rejection[52]. Additionally, xenotransplantation adheres to similar problems in T-cell and antibody responses to the porcine xenograft, requiring immunosuppression for long-term viability.

Xenotransplantation still remains in the preclinical phase of addressing the need for more organs to address the increased need that cardiac transplantation requires, but it might not be as far away as we think[5]. In January of 2022, researchers and surgeons at the University of Maryland at Baltimore successfully transplanted a genetically modified porcine cardiac xenograft into a 57-year-old male hospitalized with severe heart failure. Although patient demise occurred on post-operative day 60, it represents a large step forward for xenografts as a potential to reduce the gap between organ donors and those on the transplant waitlist[53].

CONCLUSION

As scientists continue to innovate in the field of cardiac transplantation, donor organ availability continues to plague patients with heart failure or congenital heart disease evident by high waitlist times and waitlist mortality rates. Many groundbreaking surgical techniques, biomedical technologies, and policy changes are transcending the laboratory and moving into the world of clinical medicine, not just as an attempt to provide better surgical or clinical outcomes but to provide a greater number of patients life-changing transplant medicine. Further research is needed to evaluate the short-term and long-term medical efficacy and ethical considerations of these novel transplant innovations, but the future is beginning to look brighter for patients with heart failure and/or irreparable heart valve disease.