Impact of donor-specific anti-HLA antibody on cardiac hemodynamics and graft function 3 years after pediatric heart transplantation: First results from the CTOTC-09 multi-institutional study.

The aim of this study (CTOTC-09) was to assess the impact of "preformed" (at transplant) donor-specific anti-HLA antibody (DSA) and first year newly detected DSA (ndDSA) on allograft function at 3 years after pediatric heart transplantation (PHTx). We enrolled children listed at 9 North American centers. The primary end point was pulmonary capillary wedge pressure (PCWP) at 3 years posttransplant. Of 407 enrolled subjects, 370 achieved PHTx (mean age, 7.7 years; 57% male). Pre-PHTx sensitization status was nonsensitized (n = 163, 44%), sensitized/no DSA (n = 115, 31%), sensitized/DSA (n = 87, 24%), and insufficient DSA data (n = 5, 1%); 131 (35%) subjects developed ndDSA. Subjects with any DSA had comparable PCWP at 3 years to those with no DSA. There were also no significant differences overall between the 2 groups for other invasive hemodynamic measurements, systolic graft function by echocardiography, and serum brain natriuretic peptide concentration. However, in the multivariable analysis, persistent first-year DSA was a risk factor for 3-year abnormal graft function. Graft and patient survival did not differ between groups. In summary, overall, DSA status was not associated with worse allograft function or inferior patient and graft survival at 3 years, but persistent first-year DSA was a risk factor for late graft dysfunction.

Cardiac magnetic resonance diastolic indices correlate with ventricular filling pressures in pediatric heart transplant recipients.

BACKGROUND: Atrial and ventricular filling pressures are routinely used in pediatric heart transplant (PHTx) recipients to assess graft function. We hypothesized that cardiac magnetic resonance (CMR) diastolic indices correlate with filling pressures, providing a noninvasive method of hemodynamic assessment. METHODS: Pediatric heart transplant recipients were prospectively enrolled at the time of cardiac catheterization. Pulmonary capillary wedge pressure (PCWP) and right atrial pressure (RAP) were measured. CMR included standard volumetric analysis. Filling curves were calculated by contouring every phase in the short-axis stack. Global longitudinal and circumferential strain (GLS, GCS) were calculated using feature tracking. Atrial volumes and ejection fraction were calculated from 4-chamber and 2-chamber cine images. Correlations were analyzed using Spearman's Rho; modeling was performed with multivariable logistic regression. RESULTS: A total of 35 patients with a mean age of 15.5 years were included, 12 with acute rejection. The median time post-transplant was 6.2 years. Peak filling rate (PFR) and peak LV ejection rate/end-diastolic volume (PER/EDV) correlated with PCWP (rho = 0.48 p = .005, and rho = -0.35 p = .046, respectively) as did GLS and GCS (rho = 0.52 p = .002, and 0.40 p = .01). Indexed maximum and minimum left atrial (LA) volume correlated with PCWP (rho = 0.41, p = .01, rho = 0.41 p = .01), and LA ejection fraction inversely correlated with PCWP (rho = -0.40, p = .02). GLS and GCS correlated with RAP (rho = 0.55, p = .001 and rho = 0.43, p = .01). A model including LV GLS and PFR estimated PCWP ≥12 mmHg with an area under the curve of 0.84. CONCLUSIONS: Cardiac magnetic resonance can be a useful noninvasive modality to assess for signs of diastolic dysfunction after PHTx.

Genetic Causes of Cardiomyopathy in Children: First Results From the Pediatric Cardiomyopathy Genes Study.

Background Pediatric cardiomyopathy is a genetically heterogeneous disease with substantial morbidity and mortality. Current guidelines recommend genetic testing in children with hypertrophic, dilated, or restrictive cardiomyopathy, but practice variations exist. Robust data on clinical testing practices and diagnostic yield in children are lacking. This study aimed to identify the genetic causes of cardiomyopathy in children and to investigate clinical genetic testing practices. Methods and Results Children with familial or idiopathic cardiomyopathy were enrolled from 14 institutions in North America. Probands underwent exome sequencing. Rare sequence variants in 37 known cardiomyopathy genes were assessed for pathogenicity using consensus clinical interpretation guidelines. Of the 152 enrolled probands, 41% had a family history of cardiomyopathy. Of 81 (53%) who had undergone clinical genetic testing for cardiomyopathy before enrollment, 39 (48%) had a positive result. Genetic testing rates varied from 0% to 97% between sites. A positive family history and hypertrophic cardiomyopathy subtype were associated with increased likelihood of genetic testing (P=0.005 and P=0.03, respectively). A molecular cause was identified in an additional 21% of the 63 children who did not undergo clinical testing, with positive results identified in both familial and idiopathic cases and across all phenotypic subtypes. Conclusions A definitive molecular genetic diagnosis can be made in a substantial proportion of children for whom the cause and heritable nature of their cardiomyopathy was previously unknown. Practice variations in genetic testing are great and should be reduced. Improvements can be made in comprehensive cardiac screening and predictive genetic testing in first-degree relatives. Overall, our results support use of routine genetic testing in cases of both familial and idiopathic cardiomyopathy. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01873963.

The impact of psychiatric disorders on outcomes following heart transplantation in children.

Psychiatric disorders are common in pediatric HTx recipients. However, the impact of psychiatric comorbidities on patient outcomes is unknown. We aimed to assess the impact of disorders of adjustment, depression, and anxiety on HTx outcomes in children; hypothesizing that the presence of psychiatric disorders during or preceding HTx would negatively impact outcomes. All pediatric HTx recipients ≥8 years of age who survived to hospital discharge were identified from a novel linkage between the PHIS and SRTR databases (2002-2016). Psychiatric disorders were identified using ICD codes during or preceding the HTx admission. Post-transplant graft survival, freedom from readmission, and freedom from rejection were analyzed using the Kaplan-Meier method. Multivariable Cox proportional hazard models were used to adjust for covariates. A total of 1192 patients were included, of which 133 (11.2%) had depression, 197 (16.5%) had anxiety, and 218 (18.3%) had adjustment disorders. The presence of depression was independently associated with higher rates of readmission (60.9% vs 54.1% at 6 months) (AHR 1.63, 95% CI 1.22-2.18, P = .001) and inferior graft survival (70.2% vs 83.4% at 5 years) (AHR 1.62, 95% CI 1.14-2.3, P = .007). Anxiety was independently associated with higher rates of readmission (60.4% vs 53.9% at 6 months) (AHR 1.46, 95% CI 1.09-1.94, P = .01). Anxiety and depression in the pretransplant period are independently associated with outcomes following HTx in children. Evaluation and management of psychiatric comorbidities represents an important component of care in this vulnerable population.

Rehospitalization Following Pediatric Heart Transplantation: Incidence, Indications, and Risk Factors.

Rehospitalization following pediatric heart transplantation is common. However, existing data remain somewhat limited. Using a novel linkage between administrative and clinical databases, pediatric heart transplant (HT) recipients from 29 centers who survived to discharge were retrospectively reviewed to determine the frequency, timing of, and indication for all-cause rehospitalizations in the year following transplant discharge. Of 2870 pediatric HT recipients, 1835 (63.9%) were rehospitalized in the first year post-discharge (5429 total readmissions). Rehospitalization rates varied significantly across centers (46% to 100%) and were inversely correlated to center transplant volume (r2 0.25, p < 0.01). The median number of rehospitalizations per patient was 2 (IQR 1-4) and the median time to first rehospitalization was 29 days (IQR 9-99 days). Independent risk factors for rehospitalization included younger age at HT (HR 0.99, 95% CI 0.97-0.99), congenital heart disease (HR 1.2, 95% CI 1.1-1.4), listing status 1B at transplant (HR 1.3, 95% CI 1.1-1.5), and post-transplant complications including rejection prior to discharge (HR 1.5 95% CI 1.3-1.8) and chylothorax (HR 1.3, 95% CI 1.0-1.6). Cardiac diagnoses were the most common indication for rehospitalization (n = 1600, 29.5%), followed by infection (n = 1367, 25.2%). These findings may serve to guide the development of interventions aimed at reducing post-HT hospitalizations.

Disorders of Adjustment, Mood, and Anxiety in Children and Adolescents Undergoing Heart Transplantation and the Association of Ventricular Assist Device Support.

OBJECTIVE: To assess the prevalence of psychiatric disorders and associated therapies in children during their heart transplantation admission. STUDY DESIGN: All pediatric heart transplant recipients (1999-2016) were included from a linked administrative and clinical registry database. Psychiatric disorders and associated therapies were identified using International Classification of Diseases or billing codes during the transplant admission. Data were analyzed using standard descriptive statistics. Multivariable logistic regression assessed factors independently associated with psychiatric disorders or therapies. RESULTS: A total of 3073 pediatric heart transplant recipients were included. Psychiatric disorders were present in 434 (14.1%) patients during the heart transplant admission, with adjustment disorders being the most common. Antidepressant therapy was prescribed to 212 patients (6.9%) and selective serotonin reuptake inhibitors were most commonly used. Psychiatric diagnoses (8.4% vs 18.1%; P < .001) and the use of antidepressants (4.5% vs 8.9%; P < .001) increased over time (era 1, 1999-2009 vs era 2, 2010-2016). Psychiatric disorders were present in 39.8% of patients ≥8 years of age requiring ventricular assist device support at heart transplantation. The need for ventricular assist device support was independently associated with psychiatric diagnoses (aOR, 1.57; 95% CI, 1.18-2.1; P = .002) and antidepressant therapy (aOR, 2.11; 95% CI. 1.43-3.12; P < .001). CONCLUSIONS: Psychiatric disorders are common in pediatric heart transplant recipients, especially among those bridged with ventricular assist device support. Psychiatric diagnoses and the use of antidepressants has increased over time, likely representing improved recognition of psychiatric comorbidities in this vulnerable population. Access to psychiatric services represents an important component of the multidisciplinary team caring for pediatric heart transplant recipients.

Heart Transplantation in Children with Mitochondrial Disease.

OBJECTIVES: To compare the outcomes and comorbidities of children with mitochondrial disease undergoing heart transplantation with children without mitochondrial disease. STUDY DESIGN: Using a unique linkage between the Pediatric Health Information System and Scientific Registry of Transplant Recipients databases, pediatric heart transplantation recipients from 2002 to 2016 with a diagnosis of cardiomyopathy were included. Post heart transplantation survival and morbidities were compared between patients with and without mitochondrial disease. RESULTS: A total of 1330 patients were included, including 47 (3.5%) with mitochondrial disease. Survival after heart transplantation was similar between patients with and without mitochondrial disease over a median follow-up of 4 years. Patients with mitochondrial disease were more likely to have a stroke after heart transplantation (11% vs 3%; P = .009), require a longer duration of mechanical ventilation after heart transplantation (3 days vs 1 day; P < .001), and have a longer intensive care unit stay after heart transplantation (10 vs 6 days; P = .007). The absence of a hospital readmission within the first post-transplant year was similar among patients with and without mitochondrial disease (61.7% vs 51%; P = .14). However, patients with mitochondrial disease who were readmitted demonstrated a longer length of stay compared with those without (median, 14 days vs 8 days; P = .03). CONCLUSIONS: Patients with mitochondrial disease can successfully undergo heart transplantation with survival comparable with patients without mitochondrial disease. Patients with mitochondrial disease have greater risk for post-heart transplantation morbidities including stroke, prolonged mechanical ventilation, and longer intensive care unit and readmission length of stay. These results suggest that the presence of mitochondrial disease should not be an absolute contraindication to heart transplantation in the appropriate clinical setting.

Cardiac Biomarkers in Pediatric Cardiomyopathy: Study Design and Recruitment Results from the Pediatric Cardiomyopathy Registry.

BACKGROUND: Cardiomyopathies are a rare cause of pediatric heart disease, but they are one of the leading causes of heart failure admissions, sudden death, and need for heart transplant in childhood. Reports from the Pediatric Cardiomyopathy Registry (PCMR) have shown that almost 40% of children presenting with symptomatic cardiomyopathy either die or undergo heart transplant within 2 years of presentation. Little is known regarding circulating biomarkers as predictors of outcome in pediatric cardiomyopathy. STUDY DESIGN: The Cardiac Biomarkers in Pediatric Cardiomyopathy (PCM Biomarkers) study is a multi-center prospective study conducted by the PCMR investigators to identify serum biomarkers for predicting outcome in children with dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM). Patients less than 21 years of age with either DCM or HCM were eligible. Those with DCM were enrolled into cohorts based on time from cardiomyopathy diagnosis: categorized as new onset or chronic. Clinical endpoints included sudden death and progressive heart failure. RESULTS: There were 288 children diagnosed at a mean age of 7.2±6.3 years who enrolled in the PCM Biomarkers Study at a median time from diagnosis to enrollment of 1.9 years. There were 80 children enrolled in the new onset DCM cohort, defined as diagnosis at or 12 months prior to enrollment. The median age at diagnosis for the new onset DCM was 1.7 years and median time from diagnosis to enrollment was 0.1 years. There were 141 children enrolled with either chronic DCM or chronic HCM, defined as children ≥2 years from diagnosis to enrollment. Among children with chronic cardiomyopathy, median age at diagnosis was 3.4 years and median time from diagnosis to enrollment was 4.8 years. CONCLUSION: The PCM Biomarkers study is evaluating the predictive value of serum biomarkers to aid in the prognosis and management of children with DCM and HCM. The results will provide valuable information where data are lacking in children. CLINICAL TRIAL REGISTRATION NCT01873976: https://clinicaltrials.gov/ct2/show/NCT01873976?term=PCM+Biomarker&rank=1.

Cardiac transplantation in children with Noonan syndrome.

NS and related RAS/MAPK pathway (RASopathy) disorders are the leading genetic cause of HCM presenting in infancy. HCM is a major cause of morbidity and mortality in children with Noonan spectrum disorders, especially in the first year of life. Previously, there have been only isolated reports of heart transplantation as a treatment for heart failure in NS. We report on 18 patients with NS disorders who underwent heart transplantation at seven US pediatric heart transplant centers. All patients carried a NS diagnosis: 15 were diagnosed with NS and three with NSML. Sixteen of eighteen patients had comprehensive molecular genetic testing for RAS pathway mutations, with 15 having confirmed pathogenic mutations in PTPN11, RAF1, and RIT1 genes. Medical aspects of transplantation are reported as well as NS-specific medical issues. Twelve of eighteen patients described in this series were surviving at the time of data collection. Three patients died following transplantation prior to discharge from the hospital, and another three died post-discharge. Heart transplantation in NS may be a more frequent occurrence than is evident from the literature or registry data. A mortality rate of 33% is consistent with previous reports of patients with HCM transplanted in infancy and early childhood. Specific considerations may be important in evaluation of this population for heart transplant, including a potentially increased risk for malignancies as well as lymphatic, bleeding, and coagulopathy complications.

Temporal changes in left ventricular strain with the development of rejection in paediatric heart transplant recipients.

INTRODUCTION: Myocardial strain measurements are increasingly used to detect complications following heart transplantation. However, the temporal association of these changes with allograft rejection is not well defined. The aim of this study was to describe the evolution of strain measurements prior to the diagnosis of rejection in paediatric heart transplant recipients. METHODS: All paediatric heart transplant recipients (2004-2015) with at least one episode of acute rejection were identified. Longitudinal and circumferential strain measurements were assessed at the time of rejection and retrospectively on all echocardiograms until the most recent negative biopsy. Smoothing technique (LOESS) was used to visualise the changes of each variable over time and estimate the time preceding rejection at which alterations are first detectable. RESULTS: A total of 58 rejection episodes were included from 37 unique patients. In the presence of rejection, there were decrements from baseline in global longitudinal strain (-18.2 versus -14.1), global circumferential strain (-24.1 versus -19.6), longitudinal strain rate (-1 versus -0.8), circumferential strain rate (-1.3 versus -1.1), peak longitudinal early diastolic strain rate (1.3 versus 1), and peak circumferential early diastolic strain rate (1.5 versus 1.3) (p<0.01 for all). The earliest detectable changes occurred 45 days prior to rejection with simultaneous alterations in myocardial strain and ejection fraction. CONCLUSIONS: Changes in graft function can be detected non-invasively prior to the diagnosis of rejection. However, changes in strain occur concurrently with a decline in ejection fraction. Strain measurements aid in the non-invasive detection of rejection, but may not facilitate earlier diagnosis compared to more traditional measures of ventricular function.

Extracorporeal membrane oxygenation use in the first 24 hours following pediatric heart transplantation: Incidence, risk factors, and outcomes.

Primary graft dysfunction following HTx is associated with significant morbidity and mortality. This study aimed to assess the incidence of, risk factors for, and outcomes of children requiring ECMO within 24 hours of HTx. This study utilized a linked PHIS/SRTR database of pediatric HTx recipients (2002-2016). Post-HTx ECMO was identified using inpatient billing data. Logistic regression assessed risk factors for post-HTx ECMO. Kaplan-Meier analyses assessed in-hospital mortality and post-discharge survival. A total of 2820 patients were included with 224 (7.9%) requiring ECMO. Independent risk factors for post-HTx ECMO include age <1 year (aOR: 2.2, 95% CI: 1.3-3.7, P = 0.006) or 1-5 years (aOR: 2.1, 95% CI: 1.3-3.4, P = 0.002), and ECMO support at HTx (aOR: 27.4, 95% CI: 15.2-49.6, P < 0.001). Survival to discharge decreased with increasing duration of post-HTx ECMO support; 89% for 1-3 days, 79.1% for 4-6 days, 63.2% for 7-9 days, and 18.8% for ≥10 days. There was no difference in long-term survival for patients requiring post-HTx ECMO who survived to hospital discharge (P = 0.434). There are identifiable risk factors associated with the need for ECMO in the post-HTx period. Length of time on ECMO post-HTx is strongly associated with the risk of in-hospital mortality. Patients who require ECMO early post-HTx and survive to discharge have comparable outcomes to patients who did not require ECMO.

Characteristics and Outcomes of Heart Transplantation in DiGeorge Syndrome.

DiGeorge syndrome (DGS) is commonly associated with both congenital heart disease (CHD) and immunologic abnormalities. While CHD may prompt consideration for heart transplantation (HTx), little is known about HTx management or outcomes in this group. The aim of this study was to describe the spectrum of patients with DGS who undergo HTx and report post-HTx outcomes. All pediatric HTx recipients (2002-2016) with DGS were identified using ICD codes from a linked billing and clinical registry database. Patient characteristics and outcomes were described and compared to non-DGS HTx recipients with CHD. Kaplan-Meier methods were used to assess overall survival, freedom from infection, and freedom from rejection. A total of 17 patients with DGS who underwent HTx at 12 different centers were included. Median age at HTx was 5 years (IQR 0-13 years). Steroids were used for induction in all patients in addition to thymoglobulin in 13/17 (76%) and IL2R antagonists in 3/17 (18%). Maintenance immunosuppression was a combination of tacrolimus or cyclosporine and mycophenolate or azathioprine in 16/17 (94%). Half received steroids at the time of discharge. There were six deaths (35%). The median post-HTx survival was 5.4 years with no difference in freedom from rejection, infection, or overall survival between patients with and without DGS. Patients with DGS undergoing HTx received standard immunosuppression. We found no difference in freedom from infection, rejection, or overall post-HTx survival compared to non-DGS patients, although the small size of our study resulted in limited statistical power. Given the potential for favorable outcomes, patients with DGS may be considered for HTx in the appropriate clinical setting.

Increased mortality, morbidities, and costs after heart transplantation in heterotaxy syndrome and other complex situs arrangements.

OBJECTIVES: Identify pediatric heart transplant (HT) recipients with heterotaxy and other complex arrangements of cardiac situs (heterotaxy/situs anomaly) and compare mortality, morbidities, length of stay (LOS), and costs to recipients with congenital heart disease without heterotaxy/situs anomaly. METHODS: Using linked registry data (2001-2016), we identified 186 HT recipients with heterotaxy/situs anomaly and 1254 with congenital heart disease without heterotaxy/situs anomaly. We compared post-HT outcomes in univariable and multivariable time-to-event analyses. LOS and cost from HT to discharge were compared using Wilcoxon rank-sum tests. Sensitivity analyses were performed using stricter heterotaxy/situs anomaly group inclusion criteria and through propensity matching. RESULTS: HT recipients with heterotaxy/situs anomaly were older (median age, 5.1 vs 1.6 years; P < .001) and more often black, Asian, Hispanic, or "other" nonwhite (54% vs 32%; P < .001). Heterotaxy/situs anomaly was independently associated with increased mortality (hazard ratio, 1.58; 95% confidence interval, 1.19-2.09; P = .002), even among 6-month survivors (hazard ratio, 1.86; 95% confidence interval, 1.09-3.16; P = .021). Heterotaxy/situs anomaly recipients more commonly required dialysis (odds ratio, 2.58; 95% confidence interval, 1.51-4.42; P = .001) and cardiac reoperation (odds ratio, 1.91; 95% confidence interval, 1.17-3.11; P = .010) before discharge. They had longer ischemic times (19.2 additional minutes [range, 10.9-27.5 minutes]; P < .001), post-HT intensive care unit LOS (16 vs 13 days; P = .012), and hospital LOS (26 vs 23 days; P = .005). Post-HT hospitalization costs were also greater ($447,604 vs $379,357; P = .001). CONCLUSIONS: Heterotaxy and other complex arrangements of cardiac situs are associated with increased mortality, postoperative complications, LOS, and costs after HT. Although increased surgical complexity can account for many of these differences, inferior late survival is not well explained and deserves further study.

Center Variation in Hospital Costs for Pediatric Heart Transplantation: The Relationship Between Cost and Outcomes.

There are limited published data addressing the costs associated with pediatric heart transplantation and no studies evaluating the variation in costs across centers. We aimed to describe center variation in pediatric heart transplant costs and assess the association of transplant hospitalization costs with patient outcomes. Using a linkage between the Pediatric Health Information System and Scientific Registry of Transplant Recipients databases, hospital costs were assessed for patients (< 18 years of age) undergoing heart transplantation (2007-2016). Severity-adjusted patient costs were calculated using generalized linear mixed-effects models with a random hospital intercept. Center variation in hospital cost was described after adjusting for the predicted risk of in-hospital mortality. Post-transplant survival was compared between low- and high-cost centers using Cox proportional hazard models. A total of 2156 patients were included from 24 centers. There was 3.7-fold variation in transplant hospitalization costs across centers, ranging from $329,477 to $1,226,507. Patients transplanted at high-cost centers have a higher predicted risk of in-hospital mortality (8.1% vs. 6.1%, p < 0.001). Both early (p = 0.008) and long-term (p = 0.003) post-transplant survival were better in patients transplanted at low-cost centers. Transplant at low-cost centers was associated with improved post-transplant survival, independent of patient-specific risk (adjusted hazard ratio 0.72; 95%CI 0.57-0.92, p = 0.008). There is wide variation in cost for pediatric heart transplant inpatient care among U.S. centers with low-cost centers demonstrating the best patient survival. Differences in patient populations likely contribute to these findings, but cannot account for all the variation seen. This suggests that variability in the delivery of care across centers may influence post-transplant survival.

Practice Variation, Costs and Outcomes Associated with the Use of Inhaled Nitric Oxide in Pediatric Heart Transplant Recipients.

Right ventricular (RV) failure is a potentially fatal complication following heart transplantation (HTx). Inhaled nitric oxide (iNO) is a selective pulmonary vasodilator that is used to decrease pulmonary vascular resistance immediately post-HTx to reduce the risk of RV failure. The aim of this study was to describe utilization patterns, costs, and outcomes associated with post-transplant iNO use in children. All pediatric HTx recipients (2002-2016) were identified from a unique linked PHIS/SRTR dataset. Post-HTx iNO use was determined based on hospital billing data. Utilization patterns and associated costs were described. The association of iNO support with post-HTx survival was assessed using the Kaplan-Meier method and a multivariable Cox proportional hazards model was used to adjust for risk factors. A total of 2833 pediatric HTx recipients from 28 centers were identified with 1057 (36.5%) receiving iNO post-HTx. Post-HTx iNO use showed significant increase overall (17.2-54.7%, p < 0.001) and wide variation among centers (9-100%, p < 0.001). Patients with congenital heart disease (aOR 1.4, 95% CI 1.2, 1.6), requiring mechanical ventilation at HTx (aOR 1.3, 95% CI 1.1, 1.6), and pre-transplant iNO (aOR 9.3, 95% CI 5.4, 16) were more likely to receive iNO post-HTx. The median daily cost of iNO was $2617 (IQR $1843-$3646). Patients who required > 5 days of iNO post-HTx demonstrated inferior 1-year post-HTx survival (p < 0.001) and iNO use > 5 days was independently associated with worse post-HTx survival (AHR 1.6, 95% CI 1.2, 2.1; p < 0.001). There is wide variation in iNO use among centers following pediatric HTx with use increasing over time despite significant incremental cost. Prolonged iNO use post-HTx is associated with worse survival, likely serving as a marker of residual illness severity. Further research is needed to define the populations that derive the greatest benefit from this costly therapy.

Mechanical circulatory support costs in children bridged to heart transplantation - analysis of a linked database.

BACKGROUND: Pediatric mechanical circulatory support (MCS) has evolved considerably over the past decade. Though marked improvements in waitlist survival have been realized, costs have not been reassessed. This project aimed to assess contemporary MCS costs in children bridged to heart transplant (HT). METHODS: All pediatric HT recipients (2002-2016) were identified from a unique, linked PHIS/SRTR dataset. Costs were calculated from hospital charges, inflated to 2016 Dollars and adjusted for patient-specific characteristics using generalized linear mixed-effects models. Costs and length of stay (LOS) were compared across support strategies at the time of HT (no MCS, VAD, or ECMO) with select subgroup analyses. RESULTS: A total of 2873 pediatric HT recipients were included; no MCS: 2268 (78.9%), VAD: 470 (16.4%), and ECMO: 135 (4.7%). Both VAD and ECMO were associated with greater total hospitalization costs compared to no MCS ($755,345 and $808,771 vs. $457,086; P < .001). Total costs and LOS were similar between VAD and ECMO groups; however, costs and LOS were greatest for VAD-supported patients in the pre-HT period and greatest for ECMO-supported patients post-HT. Post-HT costs and LOS were similar between patients who did not require MCS and those supported with a VAD ($324,887 and 18 days vs. $329,198 and 18 days respectively, p = NS). Outpatients with VAD support at HT demonstrated significantly lower total costs compared to those who were inpatient with continuous flow devices ($552,222 vs. $663,071, P = .003). CONCLUSIONS: MCS as a bridge to HT in children is associated with greater total costs. While costs are similar between VAD and ECMO groups, the majority of costs associated with VAD support is incurred pre-HT while ECMO costs are incurred primarily post-HT. Discharging patients on VAD support awaiting HT may represent a strategy to reduce costs in this population.

Identifying Non-invasive Tools to Distinguish Acute Myocarditis from Dilated Cardiomyopathy in Children.

There is often a diagnostic dilemma in pediatric patients presenting with depressed ventricular function, as myocarditis and dilated cardiomyopathy (DCM) of other etiologies can appear very similar. Accurate identification is critical to guide treatment and to provide families with the most accurate expectation of long-term outcomes. The objective of this study was to identify patterns of clinical presentation and to assess non-invasive measures to differentiate patients with acute myocarditis from other forms of DCM. We identified all children (< 18 years) from our institution with a diagnosis of idiopathic DCM or myocarditis based on endomyocardial biopsy or explant pathology (1996-2015). Characteristics at the time of presentation were compared between patients with a definite diagnosis of myocarditis and those with idiopathic DCM. Data collected included clinical and laboratory data, radiography, echocardiography, and cardiac catheterization data. A total of 58 patients were included in the study; 46 (79%) with idiopathic DCM and 12 (21%) with acute myocarditis. Findings favoring a diagnosis of myocarditis included a history of fever (58 vs. 15%, p = 0.002), arrhythmia (17 vs. 0%, p = 0.003), higher degree of cardiac enzyme elevation, absence of left ventricular dilation (42 vs. 7%, p = 0.002), segmental wall motion abnormalities (58 vs. 13%, p = 0.001), lower left ventricular dimension z-score (3.7 vs. 5.2, p = 0.031), and less severe depression of left ventricular systolic function. There are notable differences between patients with myocarditis and other forms of DCM that can be detected non-invasively at the time of presentation without the need for endomyocardial biopsy. These data suggest that it may be possible to develop a predictive model to differentiate myocarditis from other forms of DCM using non-invasive measures.

Changes in Pediatric Heart Transplant Hospitalization Costs Over Time.

BACKGROUND: Despite significant changes in the past decade for children undergoing heart transplantation, including the evolution of mechanical circulatory support and increasing patient complexity, costs and resource utilization have not been reassessed. We sought to use a novel linkage of clinical-registry and administrative data to examine changes in hospitalization costs over time in this population. METHODS: We identified all pediatric heart transplant recipients in a unique linked Pediatric Health Information System/Scientific Registry of Transplant Recipients data set (2002-2016). Hospital costs were estimated from charges using cost-to-charge ratios, inflated to 2016 dollars. Severity-adjusted costs were calculated using generalized linear mixed-effects models. Costs were compared across 3 eras (era 1, 2002-2006; era 2, 2007-2011; and era 3, 2012-2016). RESULTS: A total of 2896 pediatric heart transplant recipients were included: era 1, 649 (22.4%); era 2, 1028 (35.5%); and era 3, 1219 (42.1%). Extracorporeal membrane oxygenation support at transplant decreased over time, concurrent with an increase in ventricular assist device-supported patients. Between era 1 and era 2, there was an increase in pretransplant hospitalization costs (US $343 692 vs US $435 554; P < 0.001). However, between era 2 and era 3, there was a decline in total (US $906 454 vs US $767 221; P < 0.001), pretransplant (US $435 554 vs US $353 364; P < 0.001), and posttransplant (US $586 133 vs US $508 719; P = 0.002) hospitalization costs. CONCLUSIONS: Concurrent with the increase in utilization of ventricular assist device support, there has been an increase in pretransplant costs associated with pediatric heart transplantation. However, in the most recent era, costs have declined. These findings suggest the evolution of more cost-effective management strategies, which may be related to shifts in the approach to pediatric mechanical circulatory support.

Geographic Distance From Transplant Center Does Not Impact Pediatric Heart Transplant Outcomes.

BACKGROUND: Many pediatric heart transplant recipients live a significant distance from their transplant center. This results in families either traveling long distances or relying on outside physicians to assume aspects of their care. Distance has been implicated to play a role in congenital heart disease outcomes, but its impact on heart transplantation has not been reported. The aim of this study was to assess the impact of distance on pediatric heart transplant outcomes. METHODS: The Scientific Registry of Transplant Recipients database was queried for all pediatric heart transplant recipients from large US children's hospitals (1987-2014). Patients were stratified into 4 groups (<20, 20-50, 50-100, and >100 miles) based on distance. Survival curves were generated and compared using the log-rank test. Cox proportional hazards regression was performed to adjust for differences between groups. RESULTS: A total of 4768 patients were included in the analysis, of which 1435 (30.1%) were <20 miles, 940 (19.7%) were 20 to 50 miles, 806 (16.9%) were 50 to 100 miles, and 1587 (33.3%) were >100 miles from their transplant center. There was no difference in posttransplant survival based on distance after adjusting for patient age, gender, ethnicity, blood type, diagnosis, listing status, and the need for pretransplant ventricular assist device, extracorporeal membrane oxygenation, or ventilator support. CONCLUSION: There is no significant difference in graft survival after pediatric heart transplantation based on patient distance from their transplant center. Our data suggest the current strategy of transitioning some aspects of transplant care to local physicians or management from a distance does not increase posttransplant mortality risk.

Changes in left ventricular strain parameters following pediatric heart transplantation.

STE is increasingly utilized to assess strain in a variety of pathologies. Strain measurements have demonstrated utility following HTx and may aid in the detection of rejection and CAV. Strain parameters have not been well defined in the pediatric HTx population. This study aimed to describe strain in pediatric HTx recipients compared to controls and assess changes over time. All pediatric HTx recipients with available echocardiograms (2004-2015) without rejection or CAV were identified. Longitudinal and circumferential strain was measured at <1 month, 1 year, 3 years, and 5 years post-transplant and compared to controls. A total of 218 echocardiograms were analyzed in 79 HTx recipients. At <1 month post-transplant, there was a significant decrement in longitudinal strain (GLS -14.6 vs -19.2, P < .001) with concurrent augmentation of circumferential strain (GCS -27.3 vs -24.3, P = .005). By 1 year post-HTx, all strain parameters normalized and were not significantly different from the control population. In the absence of graft complications, strain parameters did not change up to 5 years post-transplant. Abnormal longitudinal strain parameters are present in the early post-HTx period with a compensatory increase in circumferential strain. These changes normalize by 1 year post-transplant and do not change over time in the absence of graft complications.