Successful explantation of children from the Berlin Heart EXCOR® ventricular assist device: A systematic review.

BACKGROUND: The Berlin Heart EXCOR® (BHE) can bridge children with severe heart failure to transplantation, but some are successfully weaned and spared transplantation. This study seeks to identify characteristics of children amenable to successful explantation with BHE support. METHODS: Preferred Reporting Items for Systematic reviews and Meta-Analyses 2020 guidelines were used. Five databases were screened for original, English articles measuring BHE support in patients <18 years old based on title and abstract. Exclusion criteria were applied: full-text availability, <10 total pediatric BHE patients, zero successful explantations from BHE, nonprimary literature, adult and pediatric results that could not be separated, and studies with overlapping patient information. Studies were analyzed with descriptive statistics. RESULTS: From 41 857 potential studies, 14 were analyzed with data from 58 hospitals on four continents from 1990 to 2020. There were 984 BHE patients. The most common diagnosis was dilated cardiomyopathy (n = 318, 32.3%), followed by congenital heart disease (n = 249, 25.3%). There were 85 (8.6%) children explanted with favorable outcomes. The underlying diagnosis was known in 44 (51.8%) cases: 14 (8.4%) of 166 cardiomyopathies, 17 (48.6%) of 35 myocarditis, and 12 (16.7%) of 72 with congenital heart disease were explanted. When the type of support was known, the rate of LVAD patients explanted was 21.3% (n = 19/89) and 2.4% (n = 1/42) of BiVAD patients were explanted. CONCLUSION: Explantation from BHE is not uncommon at 8.6%, but significant variation exists in the explantation data reported. Myocarditis and LVAD support may be populations suitable for weaning. Standardization of reporting measures and prospective registries may help identify patients suitable for this alternative to transplant and help develop weaning protocols.

The teammate trial: Study design and rationale tacrolimus and everolimus against tacrolimus and MMF in pediatric heart transplantation using the major adverse transplant event (MATE) score.

BACKGROUND: Currently there are no immunosuppression regimens FDA-approved to prevent rejection in pediatric heart transplantation (HT). In recent years, everolimus (EVL) has emerged as a potential alternative to standard tacrolimus (TAC) as the primary immunosuppressant to prevent rejection that may also reduce the risk of cardiac allograft vasculopathy (CAV), chronic kidney disease (CKD) and cytomegalovirus (CMV) infection. However, the 2 regimens have never been compared head-to-head in a randomized trial. The study design and rationale are reviewed in light of the challenges inherent in rare disease research. METHODS: The TEAMMATE trial (IND 127980) is the first multicenter randomized clinical trial (RCT) in pediatric HT. The primary purpose is to evaluate the safety and efficacy of EVL and low-dose TAC (LD-TAC) compared to standard-dose TAC and mycophenolate mofetil (MMF). Children aged <21 years at HT were randomized (1:1 ratio) at 6 months post-HT to either regimen, and followed for 30 months. Children with recurrent rejection, multi-organ transplant recipients, and those with an estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m2 were excluded. The primary efficacy hypothesis is that, compared to TAC/MMF, EVL/LD-TAC is more effective in preventing 3 MATEs: acute cellular rejection (ACR), CKD and CAV. The primary safety hypothesis is that EVL/LD-TAC does not have a higher cumulative burden of 6 MATEs (antibody mediated rejection [AMR], infection, and post-transplant lymphoproliferative disorder [PTLD] in addition to the 3 above). The primary endpoint is the MATE score, a composite, ordinal surrogate endpoint reflecting the frequency and severity of MATEs that is validated against graft loss. The study had a target sample size of 210 patients across 25 sites and is powered to demonstrate superior efficacy of EVL/LD-TAC. Trial enrollment is complete and participant follow-up will be completed in 2023. CONCLUSION: The TEAMMATE trial is the first multicenter RCT in pediatric HT. It is anticipated that the study will provide important information about the safety and efficacy of everolimus vs tacrolimus-based regimens and will provide valuable lessons into the design and conduct of future trials in pediatric HT.

Outcomes after initial heart failure consultation in Fontan patients.

BACKGROUND: Patients with Fontan failure are high-risk candidates for heart transplantation and other advanced therapies. Understanding the outcomes following initial heart failure consultation can help define appropriate timing of referral for advanced heart failure care. METHODS: This is a survey study of heart failure providers seeing any Fontan patient for initial heart failure care. Part 1 of the survey captured data on clinical characteristics at the time of heart failure consultation, and Part 2, completed 30 days later, captured outcomes (death, transplant evaluation outcome, and other interventions). Patients were classified as "too late" (death or declined for transplant due to being too sick) and/or "care escalation" (ventricular assist device implanted, inotrope initiated, and/or listed for transplant), within 30 days. "Late referral" was defined as those referred too late and/or had care escalation. RESULTS: Between 7/2020 and 7/2022, 77 Fontan patients (52% inpatient) had an initial heart failure consultation. Ten per cent were referred too late (6 were too sick for heart transplantation with one subsequent death, and two others died without heart transplantation evaluation, within 30 days), and 36% had care escalation (21 listed ± 5 ventricular assist device implanted ± 6 inotrope initiated). Overall, 42% were late referrals. Heart failure consultation < 1 year after Fontan surgery was strongly associated with late referral (OR 6.2, 95% CI 1.8-21.5, p=0.004). CONCLUSIONS: Over 40% of Fontan patients seen for an initial heart failure consultation were late referrals, with 10% dying or being declined for transplant within a month of consultation. Earlier referral, particularly for those with heart failure soon after Fontan surgery, should be encouraged.

Heterogeneous outcomes of liver disease after heart transplantation for a failed Fontan procedure.

BACKGROUND: Fontan-associated liver disease (FALD) uniformly affects patients with long-term Fontan physiology. The effect of isolated heart transplant (HT) on the course of FALD post-HT is not well understood. METHODS: We evaluated serial liver imaging pre- and post-HT to assess liver changes over time in a single-center retrospective analysis of Fontan HT recipients who had pre- and ≥1-year post-HT liver imaging. Available patient demographic and clinical data were reviewed, including available liver biopsy results. RESULTS: Serial liver imaging was available in 19 patients with a median age at HT of 12 years (range 3-23), the median age from Fontan to HT of 5.7 years (range 0.8-16), and the median time from imaging to follow up of 27 months (range 12-136 months). Pre-HT liver imaging was classified as follows: normal (n=1), congested (n=9), fibrotic (n=7), and cirrhotic (n=2). The majority of transplanted patients (15/19) had improvement in their post-HT liver imaging, including 13 patients with initially abnormal imaging pre-HT having normal liver imaging at follow-up. One patient had persistent cirrhosis at 26-month follow-up, one patient had unchanged fibrosis at 18-month follow-up, and one patient progressed from fibrosis pre-HT to cirrhosis post-HT at 136 months. No patients had overt isolated liver failure during pre- or post-HT follow-up. Liver biopsy did not consistently correlate with imaging findings. CONCLUSIONS: Post-HT liver imaging evaluation in Fontan patients reveals heterogeneous liver outcomes. These results not only provide evidence for the improvement of FALD post-HT but also show the need for serial liver imaging follow-up post-HT.

Marijuana in pediatric and adult congenital heart disease heart transplant listing: A survey of provider practices and attitudes.

Despite increasing legalization and use of marijuana, there is no consensus among pediatric heart transplant institutions or providers regarding users' eligibility for cardiac transplant. We sent a survey to pediatric and ACHD transplant providers (physicians, surgeons, transplant coordinators, and pharmacists) assessing their current institution's policies and their personal opinions about marijuana use in patients being considered for heart transplantation. Of the respondents, 84% practice in the United States and Canada. Most providers (80%) care for both pediatric and ACHD patients. Respondents included cardiologists (77%) and surgeons (11%), with the remaining being coordinators and pharmacists. Most providers (73%) reported their institution had no policy regarding marijuana use in heart transplant candidates. Only 20% of respondents' institutions consider mode of consumption, with 87% and 53% approving of oral and transdermal routes, respectively, and only 7% approving of vaporized or smoked routes. While 73% of providers would consider illegal marijuana use an absolute/relative contraindication to heart transplant listing, the number decreases to 57% for legal recreational users and 21% for legal medical users. Most providers personally believe marijuana to be physically and mentally/emotionally harmful to pediatric patients (67% and 72%, respectively). Many institutions lack a policy regarding marijuana use in pediatric and ACHD heart transplant candidates, and there is considerable disagreement among providers on the best practice. With increasing legalization and use of marijuana, each institution will have to address this issue thoughtfully to continue to provide high-quality, consistent, and equitable care for pediatric and ACHD heart transplant candidates.

Pediatric Cardiomyopathies.

Pediatric cardiomyopathies are rare diseases with an annual incidence of 1.1 to 1.5 per 100 000. Dilated and hypertrophic cardiomyopathies are the most common; restrictive, noncompaction, and mixed cardiomyopathies occur infrequently; and arrhythmogenic right ventricular cardiomyopathy is rare. Pediatric cardiomyopathies can result from coronary artery abnormalities, tachyarrhythmias, exposure to infection or toxins, or secondary to other underlying disorders. Increasingly, the importance of genetic mutations in the pathogenesis of isolated or syndromic pediatric cardiomyopathies is becoming apparent. Pediatric cardiomyopathies often occur in the absence of comorbidities, such as atherosclerosis, hypertension, renal dysfunction, and diabetes mellitus; as a result, they offer insights into the primary pathogenesis of myocardial dysfunction. Large international registries have characterized the epidemiology, cause, and outcomes of pediatric cardiomyopathies. Although adult and pediatric cardiomyopathies have similar morphological and clinical manifestations, their outcomes differ significantly. Within 2 years of presentation, normalization of function occurs in 20% of children with dilated cardiomyopathy, and 40% die or undergo transplantation. Infants with hypertrophic cardiomyopathy have a 2-year mortality of 30%, whereas death is rare in older children. Sudden death is rare. Molecular evidence indicates that gene expression differs between adult and pediatric cardiomyopathies, suggesting that treatment response may differ as well. Clinical trials to support evidence-based treatments and the development of disease-specific therapies for pediatric cardiomyopathies are in their infancy. This compendium summarizes current knowledge of the genetic and molecular origins, clinical course, and outcomes of the most common phenotypic presentations of pediatric cardiomyopathies and highlights key areas where additional research is required. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT02549664 and NCT01912534.

Moderate-severe primary graft dysfunction after pediatric heart transplantation.

BACKGROUND: PGD is a complication after heart transplantation (OHT) and a significant cause of mortality, particularly in infant recipients. Lack of standardized definition of PGD in the pediatric population makes the prevalence and magnitude of impact unclear. METHODS: ISHLT PGD consensus guidelines, which include inotrope scores and need for MCS, were applied retrospectively to 208 pediatric OHT recipients from a single institution from 1/2005-5/2016. PGD was defined as: moderate PGD-inotrope score >10 on postoperative day 1 (24-48 hours), and severe PGD-MCS within 24 hours (in the absence of detectable rejection). RESULTS: PGD occurred in 34 patients (16.3%); 14 of which had severe PGD (6.7%). Multivariate risk factors for PGD included CPB time (OR 10.3/10 min, 95% 10.05, 10.2, P = 0.03), Fontan palliation (OR 1.9, 95% 1.2, 3.97), and PCM (OR 5.65, 95% 1.52, 22.4); but not age, weight, ischemic time, or donor characteristics. Upon sub-analysis excluding patients with PCM, increased CPB was a significant multivariate risk factor (OR 10.09, 95% 9.89, 10.12, P = 0.003). Patients with PGD had decreased discharge survival compared to those without PGD (85% vs 96%, P < 0.01). Severe PGD was associated with the poorest 1-year survival (57% vs 91% without PGD, P = 0.04). CONCLUSION: Patients with prolonged CPB are potentially at risk for developing PGD. Neither infant recipients nor donor characteristics were associated with an increased risk of PGD in the current era.

Clinical practice patterns are relatively uniform between pediatric heart transplant centers: A survey-based assessment.

Clinical practice variations are a barrier to the study of pediatric heart transplants and coordination of multicenter RCTs in this patient population. We surveyed centers to describe practice patterns, understand areas of variation, and willingness to modify protocol. Pediatric heart transplant centers were identified, and one survey was completed per center. Simple descriptive statistics were used. The response rate was 77% (40 responses from 52 contacted centers, 37 with complete responses). Median center volume of respondents was eight transplants/year (IQR 3-19). Most centers reported tacrolimus (36/38, 95%) and mycophenolate mofetil (36/38, 95%) as maintenance immunosuppression. Other immunosuppression agents reported were cyclosporine (7/38, 18%), everolimus or sirolimus (3/38, 8%), and azathioprine (2/38, 5%). Overall, respondents answered similarly for questions regarding clinical practices including induction therapy, maintenance immunosuppression, and rejection treatment threshold (>85% agreement for all). Additionally, willingness to change clinical practices was over 70% for all practices surveyed (35 total respondents), and 97% of centers (36/37) were willing to participate in a RCT of maintenance immunosuppression. In conclusion, we found many similar clinical practice protocols. Most centers are willing to collaborate on a common protocol in order to participate in a RCT and support a trial investigating maintenance immunosuppression.

Allosensitization does not alter post-transplant outcomes in pediatric patients bridged to transplant with a ventricular assist device.

Patients supported with a VAD are at increased risk for sensitization. We aimed to determine risk factors for sensitization as well as the impact of sensitization on post-transplant outcomes. The UNOS database (January 2004-June 2014) was used to identify patients (≤18 yrs) supported with a durable VAD. Rates and degree of sensitization in the VAD cohort were calculated. Post-transplant survival was determined comparing outcomes of sensitized vs. non-sensitized patients. There were 3097 patients included in the study; 19% (n = 579) were bridged with a VAD. Of these, 41.8% were sensitized vs. 29.9% of the patients who were not bridged with a VAD (p < 0.001). VAD was an independent predictor of sensitization (OR 2.05 [1.63-2.57]; p < 0.001). There was no difference in sensitization based on device type (continuous vs. pulsatile flow, p = 0.990). Post-transplant survival rates between the sensitized and non-sensitized VAD patients were not different, including patients with a PRA >50% and VAD patients with a positive DSC (p = 0.280 and 0.160, respectively). In conclusion, pediatric VAD patients are more likely to be sensitized, but there was no difference in sensitization based on device type. In addition, sensitization does not appear to impact outcomes.

Transplantation in the highly sensitized pediatric patient.

Sensitization against HLA antigens is a growing problem in the field of pediatric cardiac transplantation. Although surgical outcomes for congenital heart disease have improved over the decades, these successes have added to the growing list of sensitized patients who eventually may require transplantation.Cardiac transplantation survival has improved, but morbidity and mortality secondary to HLA antibodies hinder outcome. Aside from acute hemodynamic compromise, there is compelling evidence linking sensitization and AMR with the development of CAV, a major limiting factor affecting long-term graft survival. Clinical advances have improved our understanding of the roles of antibody type, CFAs and non-CFAs, and DSAs and non-DSAs. Therapeutic strategies target both the T- and B-cell lines. Combinations that include plasmapheresis, IVIG, cyclophosphamide, and rituximab have been used in clinical studies with variable success.Two newer agents show promise, targeting both ends of the antibody-mediated spectrum: Bortezomib depletes plasma cell populations, and eculizumab blocks the terminal effects of antibody action, thus preventing myocardial cell dysfunction and death. Despite numerous diagnostic and therapeutic advances, many questions remain about the best approaches.The role of HLA antibodies remains the central target of investigation.

Hypoalbuminemia and poor growth predict worse outcomes in pediatric heart transplant recipients.

Children with end-stage cardiac failure are at risk of HA and PG. The effects of these factors on post-transplant outcome are not well defined. Using the PHTS database, albumin and growth data from pediatric heart transplant patients from 12/1999 to 12/2009 were analyzed for effect on mortality. Covariables were examined to determine whether HA and PG were risk factors for mortality at listing and transplant. HA patients had higher waitlist mortality (15.81% vs. 10.59%, p = 0.015) with an OR of 1.59 (95% CI 1.09-2.30). Survival was worse for patients with HA at listing and transplant (p ≤ 0.01 and p = 0.026). Infants and patients with congenital heart disease did worse if they were HA at time of transplant (p = 0.020 and p = 0.028). Growth was poor while waiting with PG as risk factor for mortality in multivariate analysis (p = 0.008). HA and PG are risk factors for mortality. Survival was worse in infants and patients with congenital heart disease. PG was a risk factor for mortality in multivariate analysis. These results suggest that an opportunity may exist to improve outcomes for these patients by employing strategies to mitigate these risk factors.

Stenting of the right ventricular outflow tract in the high-risk infant with cyanotic teratology of Fallot.

Neonatal tetralogy of Fallot (TOF) repair carries an increased risk of low birthweight or premature infants. Studies are investigating stents in the right ventricular outflow tract (RVOT) as an alternative to aortopulmonary shunts. The authors review their institutional experience with RVOT stenting in the high-risk infant with TOF. Data on sequential patients who received RVOT stents were reviewed, with collection of their surgical, echocardiographic, and catheterization data. Size-matched control subjects were identified and outcomes compared. Six infants went to the catheterization lab for RVOT stenting from 2008 to 2010. Five of these patients had placement of an RVOT stent after balloon dilation. The median saturations were 71% on 48% fraction of inspired oxygen (FiO2), with improvement to 94% (p < 0.001) on 39% FiO2 24 h after stent placement. As shown by echocardiography, the diameter of the median right pulmonary artery (RPA) was 2.6 mm (z-score, -3.3), and the diameter of the left pulmonary artery (LPA) was 2.0 mm (z-score, -4.5). Repeat echocardiography before surgery showed a statistically significant increase in RPA and LPA size as well as a modified McGoon ratio (p < 0.05). Four of the five patients subsequently underwent TOF repair. No stent fractures occurred. One patient had repair 10 days after stent placement secondary to stent malposition and tricuspid valve injury. The authors' experience with stents in the RVOT of TOF patients has yielded good results, with significant improvement in oxygen saturations. Patients had successful elective surgical repair and stent removal without longer cardiopulmonary bypass times or recognizable complications compared with shunted patients.

Prolonged hospital length of stay after pediatric heart transplantation: A machine learning and logistic regression predictive model from the Pediatric Heart Transplant Society.

BACKGROUND: Heart transplantation (HT) is the gold standard for managing end-stage heart failure. Multiple quality metrics, including length of stay (LOS), have been used in solid organ transplantation. However, limited data are available regarding trends and factors influencing LOS after pediatric HT. We hypothesized that various donor, peri-transplant and recipient factors affect LOS after pediatric HT. METHODS: We analyzed patients <18years at time of HT from January 2005 to December 2018 in the Pediatric Heart Transplant Society database, and examined LOS trends, defined prolonged LOS (PLOS = LOS>30days after HT), identified factors associated with PLOS and assessed outcomes. RESULTS: Of 4827 patients undergoing HT, 4414 patients were discharged and included for analysis. Overall median LOS was 19days[13,34]. Median LOS was longer in patients with congenital heart disease(CHD = 25days[15,43] than with cardiomyopathy(CM = 17days[12,27] across all ages. Median LOS in age <1year was 26-days[16,45.5] and in age >10year was 16days[11,26]. PLOS was seen in 1313 patients(30%). Patients with PLOS were younger, smaller and had longer CPB times. There was no difference in utilization of VAD at HT between groups, however, ECMO use at listing(8.45% vs 2.93%,p < 0.05) and HT was higher in the PLOS group(9.22% vs 1.58%,p < 0.05). PLOS was more common in patients with previous surgery, CHD, single ventricle physiology, recipient history of cardiac arrest or CPR, end organ dysfunction, lower GFR, use of mechanical ventilation at HT and Status 1A at HT. CONCLUSION: We present novel findings of LOS distribution and define PLOS after pediatric HT, providing a quality metric for individual programs to utilize and study in their practice.

Practice variability in pediatric heart transplantation: opportunities for collaboration.

The pediatric heart transplant population continues to grow and more centers are now providing advanced heart failure and transplant services. Though more patients are surviving after transplant, pediatric center protocols have remained relatively unchanged with limited research to guide protocol optimization. The authors explore recent literature reviewing the impact of the different approaches to pre and post-transplant care and as well as the impact these variations have on the field and future directions.

Fontan-associated protein-losing enteropathy and post‒heart transplant outcomes: A multicenter study.

BACKGROUND: The influence of Fontan-associated protein-losing enteropathy's (PLE) severity, duration, and treatment on heart transplant (HTx) outcomes is unknown. We hypothesized that long-standing PLE and PLE requiring more intensive therapy are associated with increased post-HTx mortality. METHODS: This 12-center, retrospective cohort study of post-Fontan patients with PLE referred for HTx from 2003 to 2015 involved collection of demographic, medical, surgical, and catheterization data, as well as PLE-specific data, including duration of disease, intensity/details of treatment, hospitalizations, and complications. Factors associated with waitlist and post-HTx outcomes and PLE resolution were sought. RESULTS: Eighty patients (median of 5 per center) were referred for HTx evaluation. Of 68 patients listed for HTx, 8 were removed due to deterioration, 4 died waiting, and 4 remain listed. In 52 patients undergoing HTx, post-HTx 1-month survival was 92% and 1-year survival was 83%. PLE-specific factors, including duration of PLE pre-HTx, pre-HTx hospitalizations, need for/frequency of albumin replacement, PLE therapies, and growth parameters had no association with post-HTx mortality. Immunosuppressant regimen was associated with mortality; standard mycophenolate mofetil immunotherapy was used in 95% of survivors compared with only 44% of non-survivors (p = 0.03). Rejection (53%) and infection (42%) post-HTx were common, but not associated with PLE-specific factors. PLE resolved completely in all but 1 HTx survivor at a median of 1 month (interquartile range 1 to 3 months); resolution was not affected by PLE-specific factors. CONCLUSIONS: PLE severity, duration, and treatment do not influence post-HTx outcome, but immunosuppressive regimen may have an impact on survival. PLE resolves in nearly all survivors.

Early stroke post-heart transplant is associated with decreased survival in children.

BACKGROUND: Major neurologic events (MNEs) after heart transplantation (HTx) and their effect on survival have not been well described in children. In this study we aimed to characterize early MNEs (stroke, isolated seizures not from stroke and posterior reversible leukoencephalopathy [PRES] within 1 year after primary pediatric HTx) and evaluate their impact on 1-year post-HTx survival. We hypothesized that early an MNE after HTx is associated with decreased 1-year patient survival. METHODS: We performed a pediatric, single-center, retrospective analysis of 345 consecutive patients aged 0 to 22 years who underwent primary HTx during the period from November 1, 1994 to October 31, 2015. Characteristics were compared between patients with and without early MNEs. RESULTS: Nineteen percent (65 of 345) of patients had an MNE within 1 year after HTx (median 9 days, interquartile range [IQR] 4 to 23 days). Freedom from early MNE was 97%, 85% and 80% at 1, 6 and 12 months, respectively. Of the total 65 events, stroke comprised 55.4% (n = 36), isolated seizure 29.2% (n = 19) and PRES 15.4% (n = 10). With multiple logistic regression, previous neurologic disease, infection requiring intravenous antibiotic therapy and post-operative drug-treated hypertension were found to be significant risk factors for early MNEs. Stroke (hazard ratio 4.1, IQR 2.3 to 7.6, p < 0.0001), but not seizures and PRES, was associated with decreased 1-year patient survival. CONCLUSIONS: Major neurologic events are common after pediatric HTx and usually occur within the first few weeks. Early stroke was associated with decreased 1-year survival. Potentially modifiable factors, including prior neurologic event, drug-treated hypertension and infection, were associated with increased risk of developing early MNEs.

Risk stratification to determine the impact of induction therapy on survival, rejection and adverse events after pediatric heart transplant: A multi-institutional study.

BACKGROUND: Induction therapy is increasingly being used in pediatric heart transplantation. General versus risk-adapted use remains controversial. We aimed to determine the impact of induction therapy on outcomes after stratifying patients by diagnosis and risk. METHODS: The Pediatric Heart Transplant Study (PHTS) database was used to identify patients (age ≤18 years) who underwent transplantation between January 1, 2001 and December 31, 2014. Patients were excluded if they survived <48 hours or received multiple induction agents. Patients were stratified using a multivariable model to predict 1-year mortality. Patients within the top 25% risk of predicted mortality were defined as high risk (HR) and the bottom 75% as low risk (LR). RESULTS: Of the 2,860 patients studied, 1,370 received anti-lymphocyte antibody (ALA), 707 received an interleukin-2 receptor antagonist (IL-2RA) and 783 received no induction (NI) therapy. Overall, patients with NI had lower survival (p < 0.01); however, multivariable analysis did not demonstrate an association with graft loss. Freedom from rejection was greater among LR congenital heart disease (CHD) and all cardiomyopathy (CMP) patients who received induction therapy (p < 0.01, for both), as confirmed in a multivariable analysis for CMP patients. Frequency of graft vasculopathy was higher in LR CMP patients who received NI. Freedom from infection was lower with IL-2RA in the LR groups. CONCLUSIONS: Pediatric heart transplant survival has improved in the recent era, in concert with increased use of induction therapy. Although induction therapy is associated with decreased rejection, it was not found to directly influence survival on multivariable analysis. Lower risk patients may benefit the most from induction therapy, particularly IL-2RA, which may be correlated with decreased infection and rejection in this cohort.

Development and validation of a major adverse transplant event (MATE) score to predict late graft loss in pediatric heart transplantation.

BACKGROUND: There is inadequate power to perform a valid clinical trial in pediatric heart transplantation (HT) using a conventional end-point, because the disease is rare and hard end-points, such as death or graft loss, are infrequent. We sought to develop and validate a surrogate end-point involving the cumulative burden of post-transplant complications to predict death/graft loss to power a randomized clinical trial of maintenance immunosuppression in pediatric HT. METHODS: Pediatric Heart Transplant Study (PHTS) data were used to identify all children who underwent an isolated orthotopic HT between 2005 and 2014 who survived to 6 months post-HT. A time-varying Cox model was used to develop and evaluate a surrogate end-point comprised of 6 major adverse transplant events (MATEs) (acute cellular rejection [ACR], antibody-mediated rejection [AMR], infection, cardiac allograft vasculopathy [CAV], post-transplant lymphoproliferative disease [PTLD] and chronic kidney disease [CKD]) occurring between 6 and 36 months, where individual events were defined according to international guidelines. Two thirds of the study cohort was used for score development, and one third of the cohort was used to test the score. RESULTS: Among 2,118 children, 6.4% underwent graft loss between 6 and 36 months post-HT, whereas 39% developed CKD, 34% ACR, 34% infection, 9% AMR, 4% CAV and 2% PTLD. The best predictive score involved a simple MATE score sum, yielding a concordance probability estimate (CPE) statistic of 0.74. Whereas the power to detect non-inferiority (NI), assuming the NI hazard ratio of 1.45 in graft survival was 10% (assuming 200 subjects and 6% graft loss rate), the power to detect NI assuming a 2-point non-inferiority margin was >85% using the MATE score. CONCLUSION: The MATE score reflects the cumulative burden of MATEs and has acceptable prediction characteristics for death/graft loss post-HT. The MATE score may be useful as a surrogate end-point to power a clinical trial in pediatric HT.

No Obesity Paradox in Pediatric Patients With Dilated Cardiomyopathy.

OBJECTIVES: This study aimed to examine the role of nutrition in pediatric dilated cardiomyopathy (DCM). BACKGROUND: In adults with DCM, malnutrition is associated with mortality, whereas obesity is associated with survival. METHODS: The National Heart, Lung, and Blood Institute-funded Pediatric Cardiomyopathy Registry was used to identify patients with DCM and categorized by anthropometric measurements: malnourished (MN) (body mass index [BMI] <5% for age ≥2 years or weight-for-length <5% for <2 years), obesity (BMI >95% for age ≥2 years or weight-for-length >95% for <2 years), or normal bodyweight (NB). Of 904 patients with DCM, 23.7% (n = 214) were MN, 13.3% (n=120) were obese, and 63.1% (n=570) were NB. RESULTS: Obese patients were older (9.0 vs. 5.7 years for NB; p < 0.001) and more likely to have a family history of DCM (36.1% vs. 23.5% for NB; p = 0.023). MN patients were younger (2.7 years vs. 5.7 years for NB; p < 0.001) and more likely to have heart failure (79.9% vs. 69.7% for NB; p = 0.012), cardiac dimension z-scores >2, and higher ventricular mass compared with NB. In multivariable analysis, MN was associated with increased risk of death (hazard ratio [HR]: 2.06; 95% confidence interval [CI]: 1.66 to 3.65; p < 0.001); whereas obesity was not (HR: 1.49; 95% CI: 0.72 to 3.08). Competing outcomes analysis demonstrated increased risk of mortality for MN compared with NB (p = 0.03), but no difference in transplant rate (p = 0.159). CONCLUSIONS: Malnutrition is associated with increased mortality and other unfavorable echocardiographic and clinical outcomes compared with those of NB. The same effect of obesity on survival was not observed. Further studies are needed investigating the long-term impact of abnormal anthropometric measurements on outcomes in pediatric DCM. (Pediatric Cardiomyopathy Registry; NCT00005391).