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. Author manuscript; available in PMC: 2025 Apr 1.
Published in final edited form as: Artif Organs. 2023 Oct 18;48(4):326–335. doi: 10.1111/aor.14664

Partial Heart Transplantation: Growing Heart Valve Implants for Children

Taufiek Konrad Rajab 1
PMCID: PMC10960715  NIHMSID: NIHMS1938737  PMID: 37849378

Abstract

Heart valves serve a vital hemodynamic function to ensure unidirectional blood flow. Additionally, native heart valves serve biological functions such as growth, and self-repair. Heart valve implants mimic the hemodynamic function of native heart valves, but are unable to fulfill their biological functions. We developed partial heart transplantation to deliver heart valve implants that fulfill all functions of native heart valves. This is particularly advantageous for children, who require growing heart valve implants. This invited review outlines the development of partial heart transplantation, its perceived merits, the clinical state of the art and future directions.

Graphical Abstract:

graphic file with name nihms-1938737-f0001.jpg

Heart valve replacement in babies is marred with problems because heart valve implants do not grow. Partial heart transplantation is a new approach to deliver growing heart valve implants. This invited review outlines past, present and future for partial heart transplantation.

Heart valves serve a vital hemodynamic function by ensuring unidirectional blood flow without stenosis. In order to achieve this function, the heart valve leaflets open and close approximately 70 times per minute, 100,000 times per day, and 3 billion times over a lifetime. Additionally, heart valves possess important biological functions, including growth during childhood, and self-repair of wear and tear. These functions are achieved by cells in the valve leaflets.1,2 Impairment of any of these functions causes heart valve disease, which affects approximately 75 million people worldwide.3 Frequently, treatment of heart valve disease requires heart valve implants.4 Over 280,000 new heart valve implants are used each year.5 However, conventional heart valve implants are unable to fulfill the biological functions of native heart valves. This is a critical barrier to progress in the field, particularly for the treatment of growing children.

Heart Valve Implants for Small Children

The only implants small enough for cardiac outflow valve replacement in newborns are homografts from other newborns. Homografts are sourced from human cadavers. Cadaveric homograft valve implants have been used for heart valve replacement for over half a century.6 Initially, cadaver valves procured on autopsy were used without further processing.7 Such untreated valves are known as homovital homografts.8 Subsequently, cryopreserved homografts were developed to simplify the logistics distributing homografts that are stored below −135 C.7 Both homovital homografts and cryopreserved homografts retain the valve extracellular matrix that allows their leaflets to ensure unidirectional blood flow. However, no measures are taken to maintain viability of the valve cells. While homografts may retain small amounts of viable donor cells after implantation,9–11 these cells are highly abnormal and unable to contribute to valve biological functions.12 Therefore, homografts do not grow, or self-repair. Consequently, homografts rapidly stenose as the children outgrow the grafts. Therefore, affected children are committed to incessant re-operations with serially larger implants until an adult-sized implant can fit.13,14 This approach results in rather poor outcomes. Due to the problems with heart valve replacement in newborn babies, surgeons go to extraordinary lengths to try to repair the valves before replacing the valve with an implant. By this point, long cross-clamp times result in high early mortality rates. Analysis of the Society of Thoracic Surgeons Congenital Heart Surgery Database showed that the early mortality of aortic valve replacement with homografts in neonates and infants is 40%.15 Moreover, our meta-analysis of surgical case series with persistent truncus arteriosus showed that truncal valve replacement carries an early mortality of 49% and a late mortality of 15% per year.16 Growing heart valves implants would improve morbidity and mortality by avoiding the need to attempt complex valve repairs and by decreasing future reinterventions. 17

Tissue Engineered Heart Valve Implants

The scientific status quo for developing growing heart valve implants for neonates are approaches based on tissue engineering. Tissue engineering manipulates viable cells and biomaterials to fabricates and functionalize tissue.18 However, this poses formidable challenges that resemble the reverse of carcinogenesis. In carcinogenesis, a differentiated cell abandons its role in a functional tissue, expands clonally and dissociates from its extracellular matrix scaffold. In tissue engineering, cells of sufficient number must first be expanded from a source of progenitors, as stated by Rudolf Virchow’s dictum “omnis cellula e cellula”. Next, these expanded cells need to be appropriately differentiated to arrest their expansion. Finally, the differentiated cells need to be associated with a scaffold to form functional tissues. Despite an intensive research effort involving myriad cell types, scaffolds and strategies for cellularizing the scaffolds, all tissue engineering approaches to develop growing heart valve implants have failed in clinical translation.17,19–23 Similar issues have plagued other applications for tissue engineering, such as attempts to create an artificial trachea.24,25 This has resulted in some of the biggest biomedical research scandals of our time, including the Paolo Macchiarini scandal.26

Transplantation Delivers Growing Heart Valves

Ross pulmonary autotransplants retain viable valve cells despite surgical devascularization and re-implantation. This allows neonatal Ross pulmonary autotransplant valves to grow27 and self-repair, resulting in long-term durability.28 Unfortunately, Ross pulmonary autografts have a number of drawbacks. Firstly, the Ross procedure is only feasible if the native pulmonary valve is functional. This excludes many children, such as those with truncus arteriosus or combined aortic and pulmonary valve dysfunction. Secondly, the Ross procedure involves a cadaver homograft valve implant to replace the autograft in the pulmonary position.29 This implant does not grow or self-repair. While dysfunctional valves are better tolerated in the low-pressure pulmonary circulation than the systemic circulation, failure of the pulmonary homograft to grow still commits the children to a number of implant exchanges over time.30 Thirdly, the Ross operation places the pulmonary valve under systemic pressure, which results in late autograft dilation and regurgitation in a large number of patients.31 Finally, Ross procedures in neonates are risky operations. Our meta-analysis shows that the early mortality of neonatal Ross procedures is 24%.32

Neonatal heart transplants and the valves contained in them also grow despite immune suppression.33,34 Importantly, the outflow valves of transplanted hearts retain normal cellularity and architecture,12,35 and virtually never fail.12,35–37 While there is attrition on the waitlist, short-term surgical outcomes of neonatal orthotopic heart transplants are excellent with less than 5% early mortality.38,39 Unfortunately, neonatal orthotopic heart transplant mortality reaches 35 – 50% by 20 years.38,39 Interestingly, while long-term outcomes of orthotopic heart transplants are inevitably limited by ventricular failure from coronary allograft vasculopathy40, failure of the outflow valves is exceedingly rare.12,35–37

The Case for Partial Heart Transplantation

In order to address the urgent clinical need for growing heart valve implants, we developed a new approach that is based on transplantation.41 We named this approach partial heart transplantation because only the part of the heart containing the valves is transplanted (Figure 1), while the native ventricles are spared. Unlike cadaver homografts, viability of the donor cells in partial heart transplants is maintained like in orthotopic heart transplants (Table 1). The rationale for partial heart transplantation is that Ross pulmonary autotransplants grow despite devascularization and re-implantation27 and orthotopic heart transplants grow despite immunosuppression.33,34 Importantly, failure of outflow valves in orthotopic heart transplants is exceedingly rare.12,35–37 While orthotopic heart transplant outcomes are limited by inevitable ventricular dysfunction42, partial heart transplants spare the native ventricles and are therefore expected to last a lifetime. Clinical translation of partial heart transplantation is feasible because partial heart transplantation resembles homograft valve replacement from a surgical perspective43 (Figure 2) and orthotopic heart transplantation from a transplant immunology perspective.

Figure 1.

Figure 1.

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The illustration shows that only the part of the donor heart containing the heart valves is transplanted.

Table 1.

Comparison of homografts, homovital grafts partial heart transplants, and orthotopic heart transplants

Homograft Homovital Graft Partial Heart Transplant Orthotopic Heart Transplant
Graft Heart valve Heart Valve Heart valve Whole heart
Donor Cadaver Cadaver or organ donor Organ donor Organ donor
Tissue typing No No Yes Yes
Ischemia time Long Up to Moderate Short (potentially Moderate) Short
Recipient Immunosuppression No No Yes (potentially less stringent than orthotopic heart transplants) Yes
Functional valve cells No No Yes Yes
Growth No No Yes Yes
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Figure 2.

Figure 2.

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The intraoperative photograph shows pulmonary valve partial heart transplantation (*) in a neonate with persistent truncus arteriosus.

Nomenclature

We propose the name “partial heart transplantation” for a new class of operations that involve transplantation of part of the heart only. Depending on the part of the heart that is transplanted, other more specific names may be used for the operation performed. For example, living homograft root replacement, living homograft mitral valve leaflet patch implant, or living homograft pulmonary vein graft. Partial heart transplantation is the prototype for a new class of operations designed to deliver growing implants in children, such as blood vessels or airway.

Immunosuppression for Partial Heart Transplantation

The advantages of partial heart transplants over conventional valve implants, namely growth and self-repair, are balanced with the disadvantages inherent in transplantation, namely the need for immunosuppression. Modern immunosuppression is usually well tolerated in countless patients with organ transplants and autoimmune disorders. The long-term risks from immunosuppression in partial heart transplantation are predictable based on the extensive experience from orthotopic heart transplants. In infant recipients of orthotopic heart transplants, the incidence of post-transplant lymphoproliferative disease caused by Epstein-Barr virus is 12% at 10 years and the incidence of severe renal dysfunction caused by calcineurin inhibitors is 6% at 10 years.42 However, while immunosuppression for orthotopic heart transplants can serve as a guide, the optimal level of immunosuppression for partial heart transplantation has not been determined yet. Previous studies analyzed immunosuppression with mycophenolate mofetil for 3 months after homograft use in children with regards to the HLA antibody response.44,45 Immunosuppression did not have an effect on clinical outcomes and homograft growth was not analyzed. It is likely that immunosuppression requirements for partial heart heart transplants are less stringent than for orthotopic heart transplants. In the future, determining the optimal level of immunosuppression for partial heart transplantation and development of safer immunosuppressants will continue to shift the risk-benefit ratio in favor of partial heart transplantation. Importantly, it is possible to stop immunosuppression for partial heart transplants in grown children or in case of complications. In this case, the partial heart transplants would simply turn into conventional non-growing homografts (Table 1).8,46

Donor Hearts for Partial Heart Transplantation

Another important factor to consider is the donor supply for partial heart transplantation. The most convenient source for partial heart transplant grafts are donor hearts from the Organ Procurement and Transplantation Network (OPTN). Since donor hearts are a scarce resource, using hearts from the OPTN that can also be allocated for orthotopic heart transplantation would lower the number of orthotopic heart transplants that can be performed. Therefore, additional sources for partial heart transplant grafts need to be explored. Analyses of the United Network for Organ Sharing (UNOS) database by our group and Dr. Andrew Goldstone’s group showed that the OPTN does not allocate donor hearts from approximately 30 to 40 infants and 40 to 80 toddlers per year.47,48 Common reasons for not using donor hearts from the OPTN for orthotopic heart transplantation are ventricular dysfunction, logistical challenges, and donation after cardiac death. These hearts could be used for partial heart transplantation if the heart valves are structurally normal.49 Additionally, donor hearts that are not entered into the OPTN could be used for partial heart transplantation. Donor hearts are not entered into the OPTN if organ procurement organizations (OPOs) deem the likelihood of allocation as exceedingly low. This is frequently the case with neonates smaller than 5 kg for example. These hearts could also be used for partial heart transplantation if the donors are appropriately consented by OPOs.

Of note, each donor heart can potentially serve as a source for multiple partial heart transplants. This raises ethical questions about equitable allocation of donor grafts, similar to concerns that were raised about the relative societal50 and economic51 benefit of single versus double lung transplantation.

Partial Heart Domino Transplantation

Interestingly, many orthotopic heart transplant recipients have structurally normal outflow heart valves. Many of these recipients could serve as donors for domino partial heart transplants.47 The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation records 100–160 infant orthotopic heart transplants per year, of which over 80% are done in North America.42 Approximately one third of these are done for dilated cardiomyopathy42, patients who typically have structurally normal valves.

Donor Pool for Partial Heart Transplantation

As described above, the total donor pool for partial heart transplantation is far larger than for orthotopic heart transplantation. In fact, grafts for orthotopic heart transplantation, partial heart transplantation and cadaver homograft valve replacement overlap in a relationship where all orthotopic heart transplant grafts could serve as partial heart transplants, and all partial heart transplants could serve as cadaver homografts (Figure 3).

Figure 3.

Figure 3.

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The Venn diagram shows the overlapping relationship for donors of cadaver homografts, partial heart transplant grafts and orthotopic heart transplant grafts.

Moreover, the procurement radius for partial heart transplants is also larger than for orthotopic heart transplants because longer ischemia times can be tolerated.52 Importantly, a larger donor pool translates into relatively shorter waitlist times.

Last but not least, prodigious progress in the field of xenotransplantation53 raises the promise of an unlimited supply of donor grafts. Our preliminary experiments show that partial heart xenotranplantation54–56 is feasible.

Experimental Partial Heart Transplantation

The initial hypothesis for partial heart transplantation was based on clinical evidence for growth of the valves in orthotopic heart transplants and Ross pulmonary autotransplants as outlined above.41 The rationale for proposing partial heart transplantation is that neonatal orthotopic heart transplants have far better outcomes than neonatal heart valve replacements.15,16,32,38 Unfortunately, early reactions to the hypothesis were negative. Michael Sarr, the editor-in-chief of Surgery, had solicited several commentary articles from well-known cardiac surgeons to be published alongside the original hypothesis, but due to their content it was decided to publish the hypothesis alone. After discussion with my mentors, it became clear that experimental evidence was necessary to support the hypothesis before clinical translation would be feasible. We started our research program with in vitro experiments52 and rodent heterotopic partial heart transplantation experiments.57 However, the rhodent heterotopic partial heart transplant experiments failed miserably, presumably because a second valve transplanted in series with the native aortic valve does not experience sufficient pressure differentials to open and close physiologically. Additional funding subsequently allowed us to perform experimental open-heart surgery to replace the pulmonary valve with partial heart transplants in piglets (Figure 4). These experiments unequivocally demonstrated growth of partial heart transplants in immunosuppressed recipients. In collaboration with Dr. Muhammad Mohiuddin, we also started a program to explore partial heart xenotransplantation from genetically engineered piglet donors into non-human primate recipients.54

Figure 4.

Figure 4.

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The intraoperative photograph shows partial heart transplantation from a green fluorescent protein transgenic donor piglet into a wild type recipient.

Clinical Partial Heart Transplantation

Based on the evidence described above, we obtained institutional review board approval for a clinical trial of partial heart transplantation.58 However, it was clear that children with an ideal indication for the first partial heart transplant would be rare. Therefore, we had shared the partial heart transplant hypothesis and our preliminary experimental data with several collaborators. Dr. Joseph Turek identified a prenatal patient with persistent truncus arteriosus and severely dysplastic truncal valve, whose prognosis with a conventional operation was expected to be very poor. In preparation for this operation, we explored the surgical design space for partial heart transplantation in persistent truncus arteriosus using 3D printed heart models and piglet heart specimen.43 Once a suitable donor was identified by directly contacting OPOs and intensive care units, we procured the donor heart and transported it to Duke Children’s Hospital, where Dr. Joseph Turek led the implant operation.59 Additional clinical partial heart transplants have been performed at Duke Children’s Hospital, by our group, NewYork-Presbyterian Morgan Stanley Children’s Hospital60 and Dell Children’s Medical Center61. The case at Morgan Stanley Children’s Hospital, which was led by Dr. David Kalfa, is notable because it was the first partial heart domino-transplant, a feat that was repeated shortly thereafter by Dr. Joseph Turek at Duke Children’s Hospital. The case at Dell Children’s Medical Center, which was led by Dr. Carlos Mery, is notable because it was the first partial heart transplant for an indication orther than persistent truncus arteriosus. Together this early experience shows promising clinical results. However, several issues need to be addressed before partial heart transplantation can become a routine procedure.

Logistics of Partial Heart Transplantation

The most acute barriers for routine partial heart transplantation are logistical. To facilitate routine partial heart transplantation, it will be necessary to operationalize a system for allocating partial heart transplant donors to recipients. Factors that affect equitable allocation of partial heart transplant donations include clinical urgency, indication (e.g. systemic versus pulmonary valve dysfunction), alternative treatment options, anatomical fit (e.g. valve annular diameter), immunological fit (e.g. ABO type), time on the waitlist, and distance (e.g. special provisions for local domino transplants). Currently, partial heart transplant programs independently navigate the logistical challenges of identifying partial heart transplant donors. To improve the efficiency of this process, we have formed a consortium with Duke Children’s Hospital to share information about donors and recipients. In the future, a centralized allocation system would further increase the efficiency of partial heart transplant allocation. The allocation system could either be organized similar to the distribution of homografts or similar to the distribution of organs by the OPTN.

Regulation of Partial Heart Transplantation

Allocation of partial heart transplants requires oversight and regulation. Regulation of partial heart transplantation could either follow the example of homografts regulation or the example of orthotopic heart transplant regulation. There are legal frameworks for either type of regulation. Heart valves are considered human cellular and tissue-based products (HCT/Ps).62 HCT/Ps are regulated by the Food and Drug Administration (FDA) as biological products.63 However, HCT/Ps qualify for exceptions from FDA regulation if they meet certain specific criteria.64 The criteria relevant to partial heart transplants are: the HCT/P is minimally manipulated65 (processing does not alter the original relevant characteristics of the tissue relating to its utility for reconstruction, repair, or replacement)66,67, it is intended for homologous use68 (it performs the same basic function in the recipient as in the donor), its manufacture does not involve the combination with other articles except water, crystalloids or a sterilizing, preserving or storage agent69, and it is not dependent upon the metabolic activity of living cells for its primary function70.

In contrast, to heart valves, vascularized human organs for transplantation are not considered HCT/Ps.71 Therefore, human organs are not regulated by the FDA but by the Health Resources Services Administration (HRSA) under section 301 of the National Organ Transplant Act. This act also established the OPTN to maintain a national registry for organ matching. By definition, human organs include hearts72 and subparts of hearts73. It remains to be seen how these legal frameworks will be applied with regards to regulation of partial heart transplants.

Insurance Reimbursement

Another barrier to routine partial heart transplantation is reimbursement. There are no codes to bill insurance companies for partial heart transplantation using the Current Procedural Terminology (CPT). Therefore, partial heart transplant implantation could be billed as allograft valve replacement, similar to homograft valve replacement, e.g. CPT code 33406. However, this does not cover reimbursement for partial heart transplant procurement, which typically involves air transport. Another option would be to bill partial heart transplants as orthotopic heart with a reduced modifier, e.g. CPT code 33945 with modifier 52. The advantage of this strategy is that it would reimburse for the procurement. A third option would be to use CPT code 33999 for unlisted cardiac surgery procedures and use CPT code 33440 for the Ross-Konno procedure as the comparison code for pricing. Of note, hospitals can partially offset the costs for partial heart transplantation by saving the cost for a conventional heart valve implant. For example, decellularized homografts cost up to $25,000.

Once these logistical issues have been resolved, partial heart transplantation is poised to take its place among other routine transplants. Of note, the annual number of partial heart transplants is already comparable to the annual number of face transplants and other vascularized composite allografts.74,75

Future Directions in Surgical Techniques

Partial heart transplantation is a new type of transplant that opens the door to further exploration of new operations. The technical design space for partial heart transplant operations is much broader than merely replacement of the ventriculoarterial outflow valves and theoretically includes atrioventricular inflow valves, vessels, cardiac chambers, airway, etc. Some approaches to these new operations are described below.

With regards to the atrioventricular inflow valves, the technical complexity of partial heart transplantation lies in the subvalvar apparatus. One theoretical concern with replacement of the subvalvar apparatus with a partial heart transplant similar to homograft atrioventricular valve replacement76–78 is that re-implanted donor papillary muscles would be ischemic. However, the subvalvar apparatus could be spared using several possible techniques, such as transplantation of leaflet tissue while retaining the native subvalvar papillary muscles and/or cords.

Another possible application is transplantation of blood vessels. Again, the main advantage would be adaptive growth. This might be useful in children with Tetralogy of Fallot and pulmonary atresia who require reconstruction of the branch pulmonary arteries. Another indication could be children with long-segment aortic stenosis who would benefit from a growing interposition graft. Fresh arterial homograft transplants with recipient immunosuppression were previously used for treatment of critical limb ischemia, but not with an intention for growth.79

Yet another application for partial heart transplantation is transplantation of cardiac chambers or parts of the cardiac chambers. For ventricular tissue, this would require a free grafting the myocardial territory supplied by a donor coronary. Such partial heart transplants of the cardiac chambers could be applied to single ventricle defects or used to replace infarcted areas of the ventricle. However, such vascularized partial heart transplants would be limited by transplant coronary artery vasculopathy, which makes the benefits compared to orthotopic heart transplants less clear.

Future Directions in Laboratory Investigations

In addition to exploration of new operations, it will be necessary to explore the specific transplant biology of partial heart transplants. The transplant biology of partial heart transplants differs from orthotopic heart transplants, because partial heart transplants contain only a small part of the cell types and tissue mass of orthotopic heart transplants (Figure 1). Importantly, partial heart transplants do not contain contractile myocardium. This has important clinical implications for optimal preservation strategies, and optimal levels of recipient immunosuppression. To study these questions, further investigations in vitro52 and in vivo involving small57,80 and large81,82 animal models will be necessary.

The maximum preservation time for partial heart transplants is longer than orthotopic heart transplants.52 This is because orthotopic heart transplants need to perform metabolically demanding work to pump blood immediately after implantation. In contrast, partial heart transplants primarily serve a structural function. Therefore, the energetic requirements following implantation differ substantially between partial heart transplants and orthotopic heart transplants. Longer preservation times increase the procurement radius for partial heart transplants and thereby exponentially improve the chance of matching suitable donors.

The optimal level of immunosuppression for partial heart transplants is less stringent than orthotopic heart transplants. Firstly, heart valves appear to enjoy a degree of immune privilege.83,84 For example, the outflow valves of orthotopic heart transplants are histologically12,35 and functionally85 spared from rejection. Secondly, the risk from an immune response to a partial heart transplant is far less than the risk to an orthotopic heart transplant. While acute rejection of an orthotopic heart transplant is potentially life-threatening, withdrawing immunosuppression from a partial heart transplant would merely transform it into a homovital homograft.8,46,84

Conclusions

Partial heart transplants are the only heart valve implants that can fulfill all biological functions of native heart valves, including growth and self-repair. This application for partial heart transplantation is particularly suitable for neonates and infants, but it also has selected indications for patients through adulthood.86 Moreover, partial heart transplantation of the ventriculoarterial outflow valves is a prototype for other growing implants delivered through transplantation. This strategy offers qualitatively new treatment options.

Funding

This research was supported by grants to T.K.R. from the American Association for Thoracic Surgery, the Brett Boyer Foundation, the Saving Tiny Hearts Society, the Emerson Rose Heart Foundation, the South Carolina Clinical & Translational Research Institute (NIH/NCATS UL1 TR001450), the National Institutes of Health (NIH/NHLBI grant R41 HL169059–01) and Philanthropy by Senator Paul Campbell.

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