MicroRNA Expression in the Infarcted Heart Following Neonatal Cardiovascular Progenitor Cell Transplantation in a Sheep Model of Stem Cell-Based Repair.

Myocardial infarctions affect approximately 735,000 people annually in the United States and have a substantial impact on quality of life. Neonates have an enhanced capability of repairing cardiovascular damage, while adults do not. The mechanistic basis for this age-dependent difference in regenerative capacity remains unknown. Recent studies have shown that microRNAs (miRNAs) play a significant role in regulating the regenerative ability of cardiovascular cells. This report defines the alterations in miRNA expression within the cardiovascular repair zone of infarcted sheep hearts following intracardiac injection of neonatal islet-1+ cardiovascular progenitor cells. Sheep were infarcted via left anterior descending coronary artery ligation. After 3 to 4 weeks of infarction, sheep neonatal islet-1+ cardiovascular progenitor cells were injected into the infarcted area for repair. Cell-treated sheep were euthanized 2 months following cell injection, and their hearts were harvested for the analysis of miRNA and gene expression within the cardiovascular repair zone. Ten miRNAs were differentially regulated in vivo, including miR-99, miR-100, miR-302a, miR-208a, miR-665, miR-1, miR-499a, miR-34a, miR-133a, and miR-199a. These miRNAs promote stemness, cell division, and survival. Several signaling pathways are regulated by these miRNAs, including Hippo, Wnt, and Erythroblastic Leukemia Viral Oncogene B (ERBB). Transcripts encoding Wnt, ERBB, and Neuregulin 1 (NRG1) were elevated in vivo in the infarct repair zone. Wnt5a signaling and ERBB/NRG1 transcripts contribute to activation of Yes-Associated Protein 1. MiRNAs that impact proliferation, cell survival, and signaling pathways that promote regeneration were induced during cardiovascular repair in the sheep model. This information can be used to design new approaches for the optimization of miRNA-based treatments for the heart.

Surgical palliation or primary transplantation for aortic valve atresia.

OBJECTIVE: The study objective was to describe the surgical pathway progression through adolescence of an inception cohort of neonates with aortic valve atresia managed initially with surgical palliation or primary transplantation, comparing survival and self-reported health-related quality of life. METHODS: From 1994 to 2000, 565 neonates with aortic atresia were admitted to 26 Congenital Heart Surgeons' Society hospitals and followed annually for vital status. Initial management included surgical palliation (n = 453) and primary cardiac transplantation (n = 68). PedsQL health-related quality of life questionnaires were sent cross-sectionally to a subgroup of 198 patients alive at previous follow-up, with 80 responses. RESULTS: Risk of death was initially high for both treatment strategies. However, compared with initial surgical palliation, survival with primary transplantation, including wait-list mortality, was greater and persisted long-term (65% vs 40% at 15 years; P = .002). Survival after secondary transplantation (48% at 9 years) was lower than after primary transplantation (74%). Health-related quality of life total score was lower overall than that of the general adolescent population (71 ± 16 vs 84 ± 13; P = .0001; normal = 100), but similar to that of adolescents with chronic diseases. It was similar in the surgical palliation and primary transplantation groups (70 ± 16 vs 75 ± 15; P = .3). Patients who received surgical palliation reported more symptoms (76 ± 15 vs 63 ± 18; P = .02). CONCLUSIONS: Patients receiving primary heart transplantation for aortic atresia in 1994 to 2000 experienced better survival, fewer symptoms, and equivalent quality of life compared with those undergoing initial surgical palliation. Notwithstanding the limited availability of neonatal and infant donor hearts, primary transplantation may be considered for those neonates with risk factors predictive of exceptionally poor survival after surgical palliation.

Increased sensitivity to ischemic interval of donor hearts with diminished left ventricular function.

BACKGROUND: Previous studies have demonstrated that carefully selected donor hearts (DHs) with poor left ventricular ejection fraction (EF) may be transplanted with long-term survival equivalent to hearts with normal function. The purpose of this study is to facilitate their selection. METHODS: Using the United Network for Organ Sharing database, we reviewed all adult heart transplants between January 2000 and March 2016. Regression models were developed to estimate hazard ratios with 95% confidence intervals of post-transplant 1-year mortality and failure of EF to recover at 1 year for DHs with EF ≥50%, EF 40%-49.9%, and EF 30%-30.9%. RESULTS: During the study period, 31,979 DHs were transplanted. Compared with DHs with left ventricular ejection fraction ≥50%, DHs with reduced EF were younger and had slightly lower body mass index. There were no differences in the mechanism of death between groups and no differences in recipient characteristics, except for a higher incidence of African American recipients of hearts with an EF of 40%-49.9%. Of the variables analyzed, only a 1-hour increase in ischemia time had different hazard ratios for 1-year mortality between groups, with increasing hazard as EF diminished. It was also the only variable that predicted failure of recovery of normal EF and that was in the lowest EF group. CONCLUSIONS: The impact of DH traits associated with adverse outcomes after heart transplantation that we studied are similar between DHs with EF <50% and those with EF ≥50%. However, limiting ischemic time may be even more important for DHs with diminished left ventricular function, particularly at the low end of the EF spectrum.

Primary Transplantation for Congenital Heart Disease in the Neonatal Period: Long-term Outcomes.

BACKGROUND: Primary transplantation was developed in the 1980s as an alternative therapy to palliative reconstruction of uncorrectable congenital heart disease. Although transplantation achieved more favorable results, its utilization has been limited by the availability of donor organs. This review examines the long-term outcomes of heart transplantation in neonates at our institution. METHODS: The institutional pediatric heart transplant database was queried for all neonatal heart transplants performed between 1985 and 2017. Follow-up was obtained from medical records and an annually administered questionnaire. Overall survival and time to development of complications were estimated using the Kaplan Meier method. Univariate and multivariate analyses were performed to identify independent predictors of survival. RESULTS: Heart transplantation was performed in 104 neonates. Median age was 17 days. Hypoplastic left heart syndrome (classic or variant) was the primary diagnosis in 77.8% of patients. Survival at 10 years and 25 years was 73.9% and 55.8%, respectively. At 20 years, freedom from allograft vasculopathy and lymphoproliferative disease was 72.0% and 81.9%, respectively. Freedom from re-transplantation was 81.4% at 20 years. Eight patients (7.6%) developed end-stage renal disease. By multivariate analysis, lower glomerular filtration rate and allograft vasculopathy were the only significant predictors of death. CONCLUSIONS: Neonatal heart transplantation remains a durable therapy with very acceptable long-term survival. Children transplanted in the newborn period have the potential to reach adulthood with minimal need for reintervention.

Interaction Between Ischemic Time and Donor Age on Adult Heart Transplant Outcomes in the Modern Era.

BACKGROUND: We examined the effect of cold ischemic interval on modern outcomes to determine whether advances in patient management have made an impact. METHODS: Using the United Network of Organ Sharing database, we reviewed adult heart transplants between January 2000 and March 2016. We divided donor age into terciles: younger than 18 years, 18 to 33 years, and 34 years and older. Within each tercile, transplants were divided by cold ischemic interval of less than 4 hours, 4 to 6 hours, and more than 6 hours. Survival curves were compared between cold ischemic interval categories within each tercile. Covariate-adjusted and donor age-stratified Cox proportional hazards regression models were used to estimate overall mortality and graft failure hazards ratios. RESULTS: Of 29,192 transplants, no significant differences between cold ischemic interval groups in survival or graft failure were apparent in the group aged younger than 18. For donors older than 18, significant differences were found for survival and graft failure with cold ischemic interval exceeding 4 hours in both univariate and multivariate analysis, and survival functions at different ischemic intervals continued to diverge beyond 1 year. The interaction effect between donor age and cold ischemic interval on overall mortality was not significant when analyzed as continuous variables, however younger donor age appeared to attenuate increase in overall mortality with longer cold ischemic intervals. CONCLUSIONS: Despite advances in perioperative management during the past 30 years, for donors older than 18 years, cold ischemic interval exceeding 4 hours is associated with gradual but significantly diminished survival that persists well beyond the perioperative period. Comparison to historical data suggests that advances in management have somewhat attenuated the hazard associated with longer ischemic times.

Long-term transplant outcomes of donor hearts with left ventricular dysfunction.

OBJECTIVE: Despite small single-center reports demonstrating acceptable outcomes using donor hearts with left ventricular dysfunction, 19% of potential donor hearts are currently unused exclusively because of left ventricular dysfunction. We investigated modern long-term survival of transplanted donor hearts with left ventricular dysfunction using a large, diverse cohort. METHODS: Using the United Network for Organ Sharing database, we reviewed all adult heart transplants between January 2000 and March 2016. Baseline and postoperative characteristics and Kaplan-Meier survival curves were compared. A covariates-adjusted Cox regression model was developed to estimate post-transplant mortality. To address observed variation in patient profile across donor ejection fraction, a propensity score was built using Cox predictors as covariates in a generalized multiple linear regression model. All the variables in the original Cox model were included. For each recipient, a predicted donor ejection fraction was generated and exported as a new balancing score that was used in a subsequent Cox model. Cubic spline analysis suggested that at most 3 and perhaps no ejection fraction categories were appropriate. Therefore, in 1 Cox model we added donor ejection fraction as a grouped variable (using the spline-directed categories) and in the other as a continuous variable. RESULTS: A total of 31,712 donor hearts were transplanted during the study period. A total of 742 donor hearts were excluded for no recorded left ventricular ejection fraction, and 20 donor hearts were excluded for left ventricular ejection fraction less than 20%. Donor hearts with reduced left ventricular ejection fraction were from younger donors, more commonly male donors, and donors with lower body mass index than normal donor hearts. Recipients of donor hearts with reduced left ventricular ejection fraction were more likely to be on mechanical ventilation. Kaplan-Meier curves revealed no significant differences in recipient survival up to 15 years of follow-up (P = .694 log-rank test). Cox regression analysis showed that after adjustment for propensity variation, transplant year, and region, ejection fraction had no statistically significant impact on mortality when analyzed as a categoric or continuous variable. Left ventricular ejection fraction at approximately 1 year after transplantation was normal for all groups. CONCLUSIONS: Carefully selected donor hearts with even markedly diminished left ventricular ejection fraction can be transplanted with long-term survival equivalent to normal donor hearts and therefore should not be excluded from consideration on the basis of depressed left ventricular ejection fraction alone. Functional recovery of even the most impaired donor hearts in this study suggests that studies of left ventricular function in the setting of brain death should be interpreted cautiously.

Subaortic Stenosis Resection in Children: Emphasis on Recurrence and the Fate of the Aortic Valve.

BACKGROUND: Recurrence after surgical resection of discrete subvalvar aortic stenosis in children often requires repeat operation. Risk factors for recurrence are poorly understood. We sought to determine potential risk factors for recurrence and postoperative comorbidities in the long term. METHODS: Retrospective chart review was performed on all pediatric patients who underwent surgical resection of discrete subaortic stenosis at our institution. Demographics, perioperative findings, and clinical data were analyzed for predisposing factors. RESULTS: From 1991 to 2015, a total of 104 patients underwent primary surgical resection of discrete subaortic stenosis. There were no postoperative deaths. Three (2.9%) patients required pacemaker implantation. Nine (8.4%) patients required repeat resection for recurrence of subaortic membrane over a median follow-up of 8.5 years (interquartile range: 5.9-13.5 years). Actuarial freedom from repeat resection was 100%, 94%, and 82% at one, five, and ten years, respectively. Repeat resection occurred more frequently in patients with genetic disease (37.5% vs 10.7%; P = .033) and preoperative mitral regurgitation (MR; 25% vs 1.2%; P < .001). Postoperative aortic insufficiency (AI) that was moderate or worse was associated with older age at the time of first resection (relative risk [RR]: 1.54, P < .05), moderate or severe preoperative AI (RR: 1.84, P = .002), and repeat resection of subaortic stenosis (RR: 1.90, P < .001). CONCLUSION: The majority of children who undergo surgical resection of subaortic stenosis will not experience recurrence in childhood and those who do require repeat resection may have a higher incidence of genetic disease and preoperative MR. Postoperative AI is associated with repeat resection, older age at the time of surgery, and degree of preoperative AI.

Short-term hypoxia improves early cardiac progenitor cell function in vitro.

The use of cardiovascular progenitor cells (CPCs) to repair damaged myocardium has been the focus of intense research. Previous reports have shown that pretreatments, including hypoxia, improve cell function. However, the age-dependent effects of short-term hypoxia on CPCs, and the role of signaling in these effects, are unknown. Cloned neonatal and adult CPCs expressing Isl1, c-Kit, KDR, PDGFRA, and CXCR4, were preconditioned using hypoxia (1% O2 for six hours). Intracellular signaling pathway changes were modeled using Ingenuity Pathway Analysis (IPA), while qRT-PCR, flow cytometry, and immunoblotting were used to measure pathway activation. Cellular function, including survival, cell cycle, and invasion, were evaluated using a TUNEL assay, flow cytometry, and a Transwell® invasion assay, respectively. IPA predicted, and RT-PCR and flow cytometry confirmed, that the PI3K/AKT pathway was activated following short-term hypoxia. Heat shock protein (HSP) 40 expression increased significantly in both age groups, while HSP70 expression increased only in neonatal CPCs. Neonatal CPC invasion and survival improved after hypoxia pre-treatment, while no effect was observed in cell cycling and developmental status. Prostaglandin receptor expression was enhanced in neonatal cells. Prior to transplantation, hypoxic preconditioning enhances CPC function, including invasion ability and pro-survival pathway activation.

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.

Effect of left ventricular dysfunction on utilization of donor hearts.

BACKGROUND: In this study we investigated modern, non-utilization rates of potential cardiac donors with left ventricular dysfunction (LVD) to clarify this phenomenon's magnitude and the impact of recent studies suggesting these organs can be safely transplanted. METHODS: Using the United Network for Organ Sharing transplant database, we reviewed all donors evaluated between January 1, 2007 and June 30, 2014. Exclusion criteria included lack of consent and age <13 or >59 years. The number of hearts not transplanted due to non-cardiac causes, structural disease, "other" (previous cardiac surgery, donation after cardiac death, etc.) and isolated LVD was determined and a covariates-adjusted Poisson regression model with robust standard errors was developed to estimate non-utilization relative risk (RR) with 95% confidence interval (CI) for LVD. Heart disposition for potential donor hearts was determined separately for 2 previous eras (1990 to 1999 and 2000 to 2006), and trends were evaluated. RESULTS: There were 60,789 donors assessed. Of the 44,829 organs meeting the inclusion criteria, 15,654 (34.92%) were transplanted and 29,175 (65.08%) were not. Of the non-utilized hearts, 15,512 (34.60%) were declined for non-cardiac reasons, 1,051 (2.34%) for structural disease, 4,073 (9.09%) for "other" and 8,539 (19.05%) exclusively for LVD. Of this last category, 4,950 (11.04%) lacked documented evidence of LVD. Covariates-adjusted RR for non-utilization showed that, for every 10% increase in LV ejection fraction, the risk of non-utilization decreased by 20% (RR = 0.80, 95% CI 0.79 to 0.81). Analysis of era-effect demonstrated significantly decreased overall utilization of donor hearts, with increases in the number of hearts not transplanted across all categories over time (p < 0.001). CONCLUSIONS: Roughly 20% of potential cardiac donors are excluded due to LVD. This figure has not been impacted by recent studies indicating that these hearts may be used safely. More complete data are required to understand why 11.04% of hearts that met inclusion criteria were refused for "poor function" without documented evidence.

A Hyper-Crosslinked Carbohydrate Polymer Scaffold Facilitates Lineage Commitment and Maintains a Reserve Pool of Proliferating Cardiovascular Progenitors.

BACKGROUND: Cardiovascular progenitor cells (CPCs) have been cultured on various scaffolds to resolve the challenge of cell retention after transplantation and to improve functional outcome after cell-based cardiac therapy. Previous studies have reported successful culture of fully differentiated cardiomyocytes on scaffolds of various types, and ongoing efforts are focused on optimizing the mix of cardiomyocytes and endothelial cells as well as on the identification of a source of progenitors capable of reversing cardiovascular damage. A scaffold culture that fosters cell differentiation into cardiomyocytes and endothelial cells while maintaining a progenitor reserve would benefit allogeneic cell transplantation. METHODS: Isl-1 + c-Kit + CPCs were isolated as clonal populations from human and sheep heart tissue. After hyper-crosslinked carbohydrate polymer scaffold culture, cells were assessed for differentiation, intracellular signaling, cell cycling, and growth factor/chemokine expression using real time polymerase chain reaction, flow cytometry, immunohistochemistry, and calcium staining. RESULTS: Insulin-like growth factor 1, hepatocyte growth factor, and stromal cell derived factor 1α paracrine factors were induced, protein kinase B signaling was activated, extracellular signal-regulated kinase phosphorylation was reduced and differentiation into both cardiomyocytes and endothelial cells was induced by scaffold-based cell culture. Interestingly, movement of CPCs out of the G1 phase of the cell cycle and increased expression of pluripotency genes PLOU5F1 (Oct4) and T (Brachyury) within a portion of the cultured population occurred, which suggests the maintenance of a progenitor population. Two-color immunostaining and 3-color fluorescence-activated cell sorting analysis confirmed the presence of both Isl-1 expressing undifferentiated cells and differentiated cells identified by troponin T and von Willebrand factor expression. Ki-67 labeling verified the presence of proliferating cells that remained in situ alongside the differentiated functional derivatives. CONCLUSIONS: Cloned Isl-1 + c-kit + CPCs maintained on a hyper-cross linked polymer scaffold retain dual potential for proliferation and differentiation, providing a scaffold-based stem cell source for transplantation of committed and proliferating cardiovascular progenitors for functional testing in preclinical models of cell-based repair.

Heart transplantation in children for end-stage congenital heart disease.

Heart transplantation (HT) as primary therapy for children with congenital heart disease (CHD) has become unusual. With improved early results of reconstructive surgery, the population of children and adults surviving with CHD is expanding. End-stage CHD related to myocardial dysfunction or circulation failure after prior surgery is becoming more common as an indication for HT. This heterogeneous group of CHD recipients referred for HT presents unique decision-making, technical, and physiologic challenges. Historically, a diagnosis of CHD has been a major risk factor for early mortality after HT. Rescue HT, especially in the setting of failing Fontan physiology, has the worst outcome. Early referral (before end-organ damage), proper selection, and optimization of recipients, as well as meticulous intra- and postoperative management are crucial to improving early outcomes of HT in this population. Beyond the early post-HT period, children with end-stage CHD experience long-term survival comparable to most other non-CHD recipients.

Left thoracotomy: an ideal approach for mitral valve replacement in patient with severe chest wall deformity.

We report a 65-year-old woman with chronic diastolic congestive heart failure, pulmonary hypertension, and severe mitral valve regurgitation. She was not a candidate for percutaneous mitral valve repair and was turned down for an open heart operation by 2 institutions based on her severe pectus excavatum deformity. A left posterior lateral thoracotomy approach provided excellent exposure for central cannulation and replacement of the mitral valve.

Blake drains: a novel method of chest drainage after extracardiac fontan operation with autologous pericardium.

BACKGROUND: Pleural effusions after Fontan palliation remain a cause of increased length of stay, cost, and morbidity. We report our experience with Blake drains (BDs) and the outpatient pediatric pleural drain pathway after Fontan operation. METHODS: A retrospective chart review was performed on all patients who underwent extracardiac lateral tunnel (ECLT) Fontan operation with pedicled autologous pericardium. Patients with prolonged pleural drainage were analyzed for predisposing factors. RESULTS: From March 1995 to December 2009, 162 patients (92 male, 56.8%) underwent ECLT Fontan operation. The median age at the time of Fontan operation was 30.9 months; the median weight was 12.9 kg. The median hospital stay was 4 days, and the median pleural drain requirement was 13 days. Prolonged pleural effusions occurred in 59 patients (36.4%), with prolonged cardiopulmonary bypass time identified as the only significant risk factor (p=0.04). Sixty patients (37%) were readmitted within 30 days of operation, with effusion requiring additional pleural drainage (n=41, 68.3%), infection (n=8, 13.3%), or a combination of the two (n=3, 5%) being the most common reason. There were two early deaths, neither of which was associated with BD malfunction. The BD clinical pathway for ECLT Fontan operation reduced our institutional cost to about $38,000 per patient, which represents a significant savings compared with traditional management with extended hospital stay after Fontan operation. CONCLUSIONS: Silicone BDs are safe and effective after ECLT Fontan operation. Hospital length of stay and cost can be significantly decreased when these drains are used with appropriate family involvement and close outpatient surveillance.

Isolation, Characterization, and Spatial Distribution of Cardiac Progenitor Cells in the Sheep Heart.

BACKGROUND: Laboratory large animal models are important for establishing the efficacy of stem cell therapies that may be translated into clinical use. The similarity of ovine and human cardiovascular systems provides an opportunity to use the sheep as a large animal model in which to optimize cell-based treatments for the heart. Recent clinical trials in humans using endogenous cardiovascular progenitor cells report significant improvement in cardiac function following stem cell-based therapy. To date, however, endogenous cardiovascular progenitor cells have not been isolated from the sheep heart. METHODS: Cardiovascular cells expressing SSEA-4, CD105 and c-kit were isolated by flow cytometry and cloned from the right atrium of neonatal sheep. The expression of GATA-4, c-kit, and Isl1 was identified by PCR in the cloned cells. Immunohistochemical staining was used to compare the number of SSEA-4 positive cells in the right auricle, right atrium, left ventricle and the apex of the heart of fetal, neonatal and adult sheep. The number of SSEA4+cells was also compared in fetal, pregnant and non-pregnant adult sheep. RESULTS: Four distinct cardiac progenitor cell sub-populations were identified in sheep, including CD105+SSEA-4+c-kit+Isl1+GATA-4+cells, CD105+SSEA-4+c-kit+Isl1+GATA-4-cells, CD105+SSEA-4-c-kit-Isl1+GATA-4-cells, and CD105+SSEA-4-c-kit+Isl1+GATA-4-cells. Immunohistochemical staining for SSEA-4 showed that labeled cells were most abundant in the right atrium of fetal hearts where niches of progenitor cells could be identified. CONCLUSION: We determined the phenotype and distribution of cardiac progenitor cells in the sheep heart. The availability of cloned endogenous cardiac progenitor cells from sheep will provide a valuable resource for optimizing the conditions for cardiac repair in the ovine model.

Late outcome after repair of mitral valve rupture during balloon atrial septostomy in a neonate.

Balloon atrial septostomy is ordinarily a safe palliative procedure for cyanotic congenital heart disease; however, if echocardiographic guidance is unavailable and fluoroscopy is used, distortions in the cardiac anatomy can invalidate the usual landmarks. Herein, we report iatrogenic mitral papillary muscle rupture during balloon atrial septostomy in a 4-day-old male neonate with total anomalous connection of the pulmonary veins. The anomalous connection and severe mitral regurgitation were emergently corrected, and the patient grew and developed normally. At age 24 years, he had only mild residual mitral regurgitation and was in New York Heart Association functional class I.In addition to describing the surgical treatment and positive late outcome of a rare complication, we highlight the importance of accurately evaluating balloon catheter location during atrial septostomy, especially in patients with a small left atrium.

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.

Heart transplantation for congenital heart disease in the first year of life.

Successful infant heart transplantation has now been performed for over 25 years. Assessment of long term outcomes is now possible. We report clinical outcomes for322 patients who received their heart transplant during infancy. Actuarial graft survival for newborn recipients is 59% at 25 years. Survival has improved in the most recent era. Cardiac allograft vasculopathy is the most important late cause of death with an actuarial incidence at 25 years of 35%. Post-transplant lymphoma is estimated to occur in 20% of infant recipients by25 years. Chronic kidney disease grade 3 or worse is present in 31% of survivors. The epidemiology of infant heart transplantation has changed through the years as the results for staged repair improved and donor resources remained stagnant. Most centers now employ staged repair for hypoplastic left heart syndrome and similar extreme forms of congenital heart disease. Techniques for staged repair, including the hybrid procedure, are described. The lack of donors is described with particular note regarding decreased donors due to newer programs for appropriate infant sleep positioning and infant car seats. ABO incompatible donors are a newer resource for maximizing donor resources, as is donation after circulatory determination of death and techniques to properly utilize more donors by expanding the criteria for what is an acceptable donor. An immunological advantage for the youngest recipients has long been postulated, and evaluation of this phenomenon may provide clues to the development of accommodation and/or tolerance.

In situ pericardial extracardiac lateral tunnel Fontan operation: fifteen-year experience.

BACKGROUND: The study purpose is to evaluate the long-term outcome of the in situ pericardial extracardiac lateral tunnel Fontan operation. METHODS: From June 1994 to August 2009, 160 patients with single ventricle (boys, n = 96, 60%, median age = 39 months, mean weight 15.5 kg) underwent the pedicled pericardial extracardiac lateral tunnel operation. Patients' charts were reviewed for perioperative and long-term follow-up data, outcome, and mortality. The potential growth of these tunnels was evaluated. RESULTS: The main diagnoses included tricuspid atresia (n = 44, 27%); double-outlet right ventricle (n = 29, 18%), and hypoplastic left heart syndrome (n = 26, 16%). The mean follow-up was 6.5 ± 3.7 years (range: 0.1-15 years). There were 2 (1.3%) operative and 6 (3.7%) late deaths. Actuarial survival at 14 years was 93%. Early complications included prolonged effusions (n = 35, 22%), chylothorax (n = 5, 3.1%), readmissions (n = 35, 22%), cerebrovascular accidents (n = 8, 5%), contralateral phrenic nerve palsy (n = 1, 0.8%), and transient arrhythmias (n = 5, 3.1%). No pacemaker was needed. Late complications included tunnel stenosis (n = 3, 1.8%) managed with balloon dilatation and stenting in 2 patients and surgical revision in 1; tunnel thrombosis (n = 2, 1.2%) causing death in both patients; and protein losing-enteropathy (n = 4, 2.5%). Follow-up echocardiography of 10 patients showed laminar flow, no turbulence/gradient at the inferior vena cava and mid-tunnel levels. The diameter indexed to body surface area showed growth, reduction, or no change depending on flow demands. CONCLUSIONS: The construction of the extracardiac lateral tunnel Fontan conduit using viable pedicled pericardium is a relatively simple, durable, and safe operation. Long-term follow-up confirms low morbidity and mortality. Fenestration is unnecessary in most patients. This viable tunnel adapts to physiologic flow demands.