Neonatal Heart Transplantation Research Articles

Neonatal heart transplantation in the United States: Trends and outcomes.

Heart transplantation in the neonatal period is associated with excellent survival. However, outcomes data are scant and have been obtained primarily from two single-center reports within the United States. We sought to analyze the outcomes of all neonatal heart transplants performed in the United States using the United Network for Organ Sharing (UNOS) dataset. The UNOS dataset was queried for patients who underwent infant heart transplantation from 1987 to 2021. Patients were divided into two groups based on age - neonates (<=31 days), and older infants (32 days-365 days). Demographic and clinical characteristics were analyzed and compared, along with follow up survival data. Overall, 474 newborns have undergone heart transplantation in the United States since 1987. Freedom from death or re-transplantation for neonates was 63.5%, 58.8% and 51.6% at 5, 10, and 20 years, respectively. Patients in the newborn group had lower unadjusted survival compared to older infants (p < .001), but conditional 1-year survival was higher in neonates (p = .03). On multivariable analysis, there was no significant difference in survival between the two age groups (p = .43). Black race, congenital heart disease diagnosis, earlier surgical era, and preoperative mechanical circulatory support use were associated with lower survival among infant transplants (p < .05). Neonatal heart transplantation is associated with favorable long-term clinical outcomes. Neonates do not have a significant survival advantage over older infants. Widespread applicability is limited by the small number of available donors. Efforts to expand the donor pool to include non-standard donor populations ought to be considered.

(599) Neonatal Heart Transplantation in the United States: Trends and Outcomes

(599) Neonatal Heart Transplantation in the United States: Trends and Outcomes

Successful treatment of severe autoimmune enteropathy in a pediatric heart transplant recipient with abatacept and alemtuzumab

Disorders of immune dysregulation have been reported in children who underwent heart transplantation in infancy. Diagnosis and management of such disorders are challenging. Here we describe a treatment approach to severe autoimmune enteropathy following heart transplantation in a child. Flow cytometry, TCRVβ spectratyping, microscopy and immunohistochemical staining. A 21-month-old girl with medical history of dilated cardiomyopathy necessitating heart transplantation at the age 2 months was evaluated for chronic hematochezia requiring daily transfusions of RBCs. An endoscopic biopsy showed crypt apoptosis, similar to that seen with acute graft-versus-host disease (GVHD). We hypothesized that these GVHD-like changes were caused by autoreactive T cells emerged as a consequence of neonatal thymectomy and immunosuppression. Pertinent results of work-up which supported this reasoning included: recent thymic emigrants at 0.8% of CD4+ T cells, 2% naïve and 98% memory T cells in CD45RA/RO analysis, T-cell repertoire with 15 oligoclonal families, serum ILR2α of 1,280 IU/mL and IgG of 1833 mg/dL. Despite treatment with steroids and everolimus, the patient continued to have daily hematochezia which eventually required colectomy. We approached treatment similar to that of patients with allogeneic GVHD and initiated abatacept followed by a combination of abatacept and ruxolitinib, and, finally, a combination of abatacept and alemtuzumab. Following alemtuzumab she had a clinical response with cessation of gastrointestinal bleeding and entered remission on abatacept as a maintenance therapy. We believe this is the first case of successful treatment of severe autoimmune enteropathy following a neonatal heart transplantation with the combination of abatacept and alemtuzumab.

Neonatal heart transplant outcomes: A single institutional experience

ObjectiveNeonatal orthotopic heart transplantation was introduced in the 1980s as a treatment for complex congenital heart disease. Progress in single-ventricle palliation and biventricular correction has resulted in a decline in neonatal heart transplant volume. However, limited reports on neonatal heart transplants have demonstrated favorable outcomes. We report the long-term outcomes of patients with neonatal heart transplants at our institution spanning nearly 30 years. MethodsA retrospective analysis of neonatal heart transplants and neonates listed for transplant was performed at Children's Hospital Colorado. Primary outcomes were early and late survival. Secondary outcomes were rejection episodes, retransplantation, and development of cardiac allograft vasculopathy or post-transplant lymphoproliferative disease. ResultsA total of 21 neonates underwent orthotopic heart transplantation at our institution. Among these, 10 neonates were transplanted from 1991 to 2000, 8 neonates were transplanted from 2001 to 2010, and 3 neonates were transplanted from 2011 to 2020. The average age of these patients was 17 days, and the average weight was 3.43 kg. Early survival was 95.2%. Survival at 1 and 5 years was 85.7% (confidence interval [CI], 61.9%-95.2%) and 75% (CI, 45.6%-85.5%), respectively. Of eligible patients, the 10-year and 20-year survival was 72.2% (CI, 45.1%-85.3%) and 50% (CI, 25.9%-70.1%), respectively. ConclusionsOur institution reports favorable outcomes of neonatal heart transplantation. These results should be considered within the context of outcomes for patients awaiting transplant and the limited donor availability. However, the successful nature of these procedures suggest it may be necessary to reevaluate the indications for neonatal heart transplantation, particularly where risk of mortality and morbidity with palliative or corrective surgery is high.

Stage 1 Palliation of Hypoplastic Left Heart Syndrome: What the Pediatric Anesthesiologist Needs to Know

The purpose of this review is to discuss the features of stage 1 palliation of hypoplastic left heart syndrome (HLHS). Comparison will be made between traditional surgical approaches and hybrid approaches. Anesthetic considerations for infants with these types of palliations will be discussed. While historically surgical palliation in the neonatal period or neonatal heart transplant has been the primary means of survival for neonates with HLHS, in the last two decades, more centers have been performing hybrid palliation of this defect. This palliation can be performed with the expectation that a comprehensive second-stage palliation will be done in the next several months, or it can be used as a bridge to transplant. Other uses are also being explored as research continues. Advances in the care of neonates with HLHS have led to increased survival. As surgical technique and non-surgical care of these infants continue to improve, the pediatric anesthesiologist will need to be familiar with the anatomic and physiologic implications of the various types of palliation.

Neonatal heart transplantation.

Neonatal heart transplantation was developed and established in the 1980's as a durable modality of therapy for complex-uncorrectable heart disease. Patients transplanted in the neonatal period have experienced unparalleled long-term survival, better than for any other form of solid-organ transplantation. However, the limited availability of neonatal and young infant donors has restricted the indications and applicability of heart transplantation among newborns in the current era. Indications for heart transplantation include congenital heart disease not amenable to other forms of surgical palliation, and cardiomyopathy, including some primary tumors. Use of ABO-incompatible transplants, and organs with prolonged cold ischemic time or marginal function have all been associated with good outcomes in infants. These extended strategies to increase the donor pool may also someday include donation after determination of circulatory death and the use of anencephalic donors. The operative techniques for donors and recipients of neonatal heart transplantation are unique and have been well-described. Immunosuppression protocols for neonates need not include induction and are largely steroid-free. Newborn and young infant transplant recipients have fewer episodes of rejection, less coronary allograft vasculopathy, less post-transplant lymphoproliferative disease and less renal dysfunction than their older counterparts. Long-term outcomes have been very encouraging in terms of graft survival, patient survival, and quality of life. Our review highlights the history, current indications, techniques and outcomes of heart transplantation in this immunologically-privileged subset of patients.

Cardiac transplantation in a neonate-First case in Switzerland and European overview

Twenty-four percent of pediatric heart transplantations (pHTx) are carried out in infants. Neonatal heart transplantation is both rarely performed and challenging. We report on a newborn baby girl suffering from cardiac failure due to a huge tumor (24×52mm) within the free wall of the left ventricle (LV) and subtotal obstruction of the main left bronchus. Following a surgical tumor resection, a Berlin Heart EXCOR left ventricular assist device was implanted as the bridge to the transplantation. In spite of an organ donor/recipient mismatch of >200%, both heart transplantation and the postoperative course were successful. In addition to this case report, the authors also present data from a survey on performed infant and neonatal transplantations in Western Europe. As neonatal heart transplantation is a rare event in Europe, the authors think it is of crucial importance to share this limited experience. We discuss an alternative strategy-namely, palliative surgical correction using the Fontan pathway. The challenges of donor/recipient weight mismatch and the possibilities of overcoming infant donor organ shortage as a postoperative immunosuppressive regimen are discussed as well.

Development of a Vascularized Heterotopic Neonatal Rat Heart Transplantation Model

Background/Purpose: Rodent adult-to-adult heterotopic heart transplantation is a well-established animal model, and the detailed surgical technique with several modifications has been previously described. In immature donor organ transplantation, however, the surgical technique needs to be revised given the smaller size and fragility of the donor graft. Here, we report our surgical technique for heterotopic abdominal (AHTx) and femoral (FHTx) neonatal rat heart transplantation based on an experience of over 300 cases. Methods: Heterotopic heart transplantation was conducted in syngeneic Lewis rats. Neonatal rats (postnatal day 2-4) served as donors. AHTx was performed by utilizing the conventional adult-to-adult transplant method with specific modifications for optimal aortotomy and venous anastomosis. In the FHTx, the donor heart was vascularized by connecting the donor's aorta and pulmonary artery to the recipient's right femoral artery and vein, respectively, in an end-to-end manner. A specifically fashioned butterfly-shaped rubber sheet was used to align the target vessels properly. The transplanted graft was visually assessed for its viability and was accepted as a technical success when the viability met specific criteria. Successfully transplanted grafts were subject to further postoperative evaluation. Forty cases (AHTx and FHTx; n = 20 each) were compared regarding perioperative parameters and outcomes. Results: Both models were technically feasible (success rate: AHTx 75% vs. FHTx 70%) by refining the conventional heterotopic transplant technique. Injury to the fragile donor aorta and congestion of the graft due to suboptimal venous connection were predominant causes of failure, leading to refractory bleeding and poor graft viability. Although the FHTx required significantly longer operation time and graft ischemic time, the in situ graft viabilities were comparable. The FHTx provided better postoperative monitoring as it enabled daily graft palpation and better echocardiographic visualization. Conclusions: We describe detailed surgical techniques for AHTx and FHTx while addressing neonatal donor-specific issues. Following our recommendations potentially reduces the learning curve to achieve reliable and reproducible results with these challenging animal models.

(924) - Cardiac Allograft Vasculopathy in Young Adults Who Underwent Heart Transplant in Childhood - A Serial Intravascular Ultrasound Study

(924) - Cardiac Allograft Vasculopathy in Young Adults Who Underwent Heart Transplant in Childhood - A Serial Intravascular Ultrasound Study

Severe calcification of the aorta (porcelain aorta) associated with sarcoidosis in a pediatric heart transplant recipient

We report a unique case of severe calcification of the aorta, bilateral coronary ostial stenoses and calcification of the mitral valve and left ventricle due to sarcoidosis. The patient underwent neonatal orthotopic heart transplantation secondary to hypoplastic left heart syndrome and developed hypercalcemia with other features of sarcoidosis at 10 yr of age. The mechanism for severe extra-renal calcification localized to the allograft is poorly understood, but may involve discordant local immune modulation and/or calcification-regulation between graft and host tissues.

Origins of Neonatal Heart Transplantation: An Historical Perspective

Clinical heart transplantation was first accomplished by Christiaan Barnard in 1967. Infant heart transplantation was first attempted by Adrian Kantrowitz just 3 days later in New York. Sixteen years lapsed before neonatal transplantation was again attempted, first in London and then in Loma Linda, California in the summer and fall of 1984, respectively. The latter infant became known as "Baby Fae." Neither infant survived a month, but both produced an important impact through media exposure on the public consciousness. The idea of infant organ donation slowly developed traction. The first successful neonatal heart transplant occurred in Loma Linda on November 15, 1985. That recipient, born with hypoplastic left heart syndrome, is now 25 years old. Thereafter, the incidence of infant and pediatric heart transplantation gradually increased. Today, 350 to 450 transplants are reported annually to the Registry of the International Society for Heart and Lung Transplantation, 25% of which are in young infants. Norwood's staged-reconstruction for complex univentricular heart disease has markedly reduced the need for primary transplantation in very early life. Still, many potential young infant recipients are best treated in no other way.

Does ABO-incompatible and ABO-compatible neonatal heart transplant have equivalent survival?

A best evidence topic (BET) in cardiac surgery was written according to a structured protocol. The question addressed was whether ABO-incompatible (ABO-I) heart transplant recipients have a similar survival rate as an ABO-compatible (ABO-C) transplant in the pediatric population <1 year of age. Altogether more than 112 papers were found using the reported search, of which 10 represented the best evidence to answer the clinical question. Generally, ABO-I transplantation has been associated with the neonatal population because of the relative immaturity of the immune system for the first year of life. In the BET the search-term 'pediatric' was used as a method to ensure retrieval all relevant papers. However, the vast majority of the patients reviewed were <1 year of age with specific techniques undertaken to modulate preoperative, intraoperative and postoperative isohemagglutinin titer levels with rejection monitoring. Therefore, the BET conclusions should not be applied to the pediatric group as a broad age classification. Two large series are of particular interest. Patel et al. reviewed all primary heart transplantation recipients < or =1 year of age in the United Network for Organ Sharing/Organ Procurement and Transplantation Network (UNOS/OPTN) registry (ABO-I=35 vs. ABO-C=556). There was no difference in 30-day mortality (ABO-I=5.9% vs. ABO-C=8.8%; P=0.55); one-year mortality (ABO-I=16.6% vs. ABO-C=14.7%; P=0.77); graft rejection (ABO-I=1 vs. ABO-C=0); and graft failure (ABO-I=24% vs. ABO-C=24%; P>0.99). Three-year Kaplan-Meier survival was 70% (P=0.85). Propensity score adjusted analysis did not implicate ABO-I as a predictor of mortality [hazard ratio (HR)=3.6, confidence interval (CI): 0.2-49.0; P=0.33]. The ABO-I group demonstrated an increased need for pacemaker (ABO-I=3.1% vs. ABO-C=0.4%; P=0.03) and higher stroke rate (ABO-I=12.9% vs. ABO-C=1.3%; P<0.0001). Dipchand et al. published the results of the Toronto cohort from 1992 to 2006 (ABO-I=16 vs. ABO-C=38). The median age at transplantation (ABO-I=88 days vs. ABO-C=84 days; P=0.82) and the number of neonatal transplant recipients (ABO-I=17% vs. ABO-C=22%; P=0.59) was similar. The freedom from post-transplantation death or retransplantation was equivalent at one year (ABO-I=77% vs. ABO-C=84%) and seven years (ABO-I=74% vs. ABO-C=74%; P=0.87). No significant difference was observed for the five-year freedom from: rejection (ABO-I=60% vs. ABO-C=45%; P=0.41); renal dysfunction (ABO-I=67% vs. ABO-C=72%; P=0.70); allograft vasculopathy (ABO-I=87% vs. ABO-C=78%; P=0.45); and post-transplantation lymphoproliferative disorder (PTLD) (ABO-I=87% vs. ABO-C=86%; P=0.93). We conclude that ABO-I transplantation is comparable to ABO-C transplantation, with several retrospective papers concluding there is no difference in mortality, morbidity or graft failure in the pediatric population <1 year of age.

Competing Outcomes After Neonatal and Infant Wait-listing for Heart Transplantation

Neonatal and infant heart transplantation is a therapeutic option for patients with end-stage cardiac lesions, yet infants continue to face a considerable shortage of donor organs. We sought to ascertain outcomes after listing for heart transplantation using a competing outcomes methodology, and to identify factors predicting each outcome. Review of the Toronto cardiac transplant database was undertaken to identify infant patients (<or=12 months) wait-listed for heart transplantation. Achievement of one of five possible outcomes was parametrically modeled, including: transplantation; death on the wait-list; delisting: too sick; delisting: clinically improved; and delisting for surgical palliation. Forty-three percent (117 of 269) of the total patient listings were infants (26 fetal/63 neonatal). Of the 117 patients, 80 (68%) underwent transplantation, 15 died on the wait-list, 9 were delisted (too sick/no longer eligible for transplant), 9 opted for surgical palliation and 4 were delisted (clinical improvement). Eighty-nine percent of outcomes were achieved by 3 months from listing. Blood group and transplant era predicted achieving transplantation. Factors predicting death on the wait-list included Canadian Status 4 (most urgent), and mechanical support. Status at listing also predicted delisting: too sick. Fetal listing predicted delisting for surgical alternative. The first 3 months after listing are critical for achieving an outcome, particularly in higher status patients, affirming the need for timely organ replacement. Strategies such as ABO-incompatible transplantation continue to decrease wait-list mortality; however, these data demonstrate that blood type O and B patients continue to face longer wait-list duration. It is imperative that we continue to seek solutions for the shortage of infant donor organs in order to maximize the utility of heart transplantation as a therapeutic option.

Geometric Disproportion of Cardiac Structure and Graft Ischemia Affect Tricuspid Valve Regurgitation Early After Neonatal Heart Transplantation

Although tricuspid valve regurgitation (TR) after heart transplantation is a known complication, there has been little discussion of this subject in neonatal heart transplantation. We aim to elucidate the prevalence, etiology, and evolution of TR early after transplant in neonates. Eighty-five neonatal recipients were studied retrospectively by two-dimensional and Doppler echocardiography. The semiquantitative grading of TR was based on the ratio of regurgitation jet area to right atrial area. Immediately after neonatal heart transplantation, TR was recognized in 47 patients (grade 1, n = 18; grade 2, n = 22; grade 3, n = 7; and grade 4, n = 0). Tricuspid regurgitation prevalence diminished from 55% to 19% with reduction in severity 1 year after transplantation. The prevalence of TR (grade 2 and grade 3) was affected by a donor/recipient body weight ratio of more than 2.0 (p = 0.004) and graft ischemia for more than 3 hours (p = 0.014). The ratio of donor and recipient right atria portion, which had a correlation with donor/recipient body weight ratio (r2 = 0.415, p < 0.0001), separated the four subgroups in terms of TR grade immediately after transplantation (p = 0.0064) and also at 1 year after transplantation in all surviving grafts from 1.48 +/- 0.54 to 0.8 +/- 0.32 (p < 0.0001). The Cox model found no significance for early posttransplant TR as a risk factor for graft survival. Early posttransplant TR was affected by atria geometrical disproportion and by graft ischemia. Tricuspid regurgitation was not a risk factor for graft survival because of its amelioration over time, perhaps induced by recipient growth and recovery of myocardial injury relating to graft procurement.

Heart Transplantation in Neonates: Achievements, Controversies, and Challenges for the Future

After completing this article, readers should be able to: 1. Compare the results of pediatric heart transplantation with those of transplantation in adults, including the survival rates. 2. Compare and contrast the indications for pediatric heart transplant among those younger and older than 1 year of age. 3. List the common complications after pediatric heart transplantation. 4. Compare and contrast new immunosuppressive agents (tacrolimus, mycophenolate, humanized anti-Tac antibodies) and standard therapies (cyclosporine, azathioprine, prednisone, antithymocyte globulin). 5. Describe the controversy surrounding the proper management of infants who have hypoplastic left heart syndrome. Not long after the first successful human heart transplant was performed, the first neonatal heart transplant was attempted. In December of 1967, Kantrowitz and colleagues at Maimonides Hospital in New York transplanted the heart of an anencephalic infant into a 3-week-old who had tricuspid atresia. Although the recipient survived only 6.5 hours, the technical feasibility of cardiac transplantation in the pediatric patients was proven. Thirty-three years later, heart transplantation has gained widespread acceptance as a standard treatment modality for end-stage cardiomyopathy or noncorrectable congenital heart disease in infants and children. The 2 years following Barnard’s pioneering first transplant saw explosive growth in the field of adult heart transplantation, but poor 1-year survival dampened much of the initial enthusiasm and with it, any hope for bringing heart transplantation to the pediatric population. Most centers eventually abandoned the procedure, and many physicians denounced the concept. However, a few centers persisted, most notably Dr Norman Shumway and colleagues at Stanford, gradually improving survival through strong collaborations with basic immunologists and cardiac pathologists. By the mid-1970s, heart transplantation had been extended successfully to teenagers. The introduction of the “wonder drug” cyclosporine in 1980 so dramatically improved survival in adult cardiac transplant recipients that the extension of transplantation to even younger patients became feasible. Almost as important as …

Decreased prevalence of hypoplastic left heart syndrome in Malta.

Hypoplastic left heart syndrome (HLHS) is the most severe form of congenital heart disease (CHD), which until recently was considered to be fatal. However, surgical intervention is now possible using neonatal heart transplantation or three-stage palliative surgery (Norwood's staged operations). In Malta, during the period 1977-1994, there were four cases of classic HLHS, with an additional three cases of HLHS-like cases. The birth prevalence of classical HLHS was 0.04 per 1000 live births, whereas that of combined HLHS-like cases was 0.06 per 1000 live births for the same period. One neonate with HLHS is expected every 3 or 4 years. Despite a high rate of ascertainment of CHD, the birth prevalence of HLHS in Malta was significantly lower than that quoted in historical studies (p < 0.006) and in the European Congenital Anomalies and Twins Registry (p < 0.002). Malta has the expected birth prevalence of CHD, but the spectrum of CHD exhibits a predominance of lesions causing right ventricular outflow obstruction and a deficit of lesions causing left ventricular outflow tract obstruction. CHD is caused by a genetic-environmental interaction. The low rate of HLHS in Malta appears to be a true divergence from the usual observed spectrum of CHD and may be caused by genetic and/or environmental factors.

Rapamycin (sirolimus) inhibits heart cell growth in vitro.

The success of infant and neonatal heart transplantation has increased dramatically since the mid-1980s. This success is due both to improved medical and surgical techniques and better pharmacological management of rejection episodes. We report here the results of in vitro studies designed to investigate the effect of rapamycin (a macrolide antibiotic with potent antirejection activity) on the proliferation of fetal cardiac myocytes. Our data suggest that rapamycin inhibits the proliferation of these cells, which is an effect that appears to be irreversible. This inhibition is relevant to the use of rapamycin in the treatment of rejection episodes in the infant and neonate, in which cardiac myocyte development is incomplete.

Fetal tissue typing in anticipation of neonatal heart transplantation

Background: Hypoplastic left heart syndrome is among the most common major congenital cardiac anomalies. Fetuses with this anomaly survive but require either reconstructive surgery or heart transplantation postnatally.Case: A woman whose fetus was diagnosed with hypoplastic left heart syndrome underwent funipuncture for fetal tissue typing. The fetus then was listed for heart transplantation. Once an ABO-compatible donor heart was procured, the fetus was delivered and immediately underwent transplantation.Conclusion: In candidates for neonatal heart transplantation, fetal tissue typing allows the search for an ABO-compatible donor heart to begin earlier. This approach minimizes the morbidity associated with postnatal waiting and allows transplantation to take place while the neonate is less immunocompetent.

FETAL TISSUE TYPING IN ANTICIPATION OF NEONATAL HEART TRANSPLANTATION

In Brief Background Hypoplastic left heart syndrome is among the most common major congenital cardiac anomalies. Fetuses with this anomaly survive but require either reconstructive surgery or heart transplantation postnatally. Case A woman whose fetus was diagnosed with hypoplastic left heart syndrome underwent funipuncture for fetal tissue typing. The fetus then was listed for heart transplantation. Once an ABO-compatible donor heart was procured, the fetus was delivered and immediately underwent transplantation. Conclusion In candidates for neonatal heart transplantation, fetal tissue typing allows the search for an ABO-compatible donor heart to begin earlier. This approach minimizes the morbidity associated with postnatal waiting and allows transplantation to take place while the neonate is less immunocompetent. Fetal tissue typing allows time to search for a compatible heart and reduces the mortality associated with prolonged postnatal waiting for transplant.

Newborn and infant heart transplantation.

Over a decade has passed since the first successful neonatal heart transplant was performed for palliation of hypoplastic left heart syndrome. Although neonates and infants represent a growing group of pediatric heart transplant recipients, survival remains inferior to that in older children. Decisions regarding transplantation in infancy pose unique problems for the pediatric cardiologist, including limited donor availability, pre-and posttransplant management, and improving results of alternative palliative surgery for hypoplastic left heart syndrome. A number of recent articles provide important information about donor availability, waiting times to transplantation, and outcome after listing and transplantation. Other studies focus on the treatment of infants awaiting transplantation. Important laboratory investigations reported this year focus on strategies for inducing immunologic tolerance (the "Holy Grail" of the transplant physician) as well as ongoing research in the controversial area of xenotransplantation.