Long-term studies on safety of beta-blockers in pediatric heart failure (HF) are scant. We describe the safety profile, dose ranges, and tolerability of carvedilol in pediatric dilated cardiomyopathy (DCM). The Pediatric Cardiomyopathy Registry (PCMR) was used to identify patients with DCM, treated with carvedilol from 1997 to 2005. Descriptive statistics were analyzed and echocardiographic parameters were compared longitudinally using ANOVA. Total 118 patients were included with median age 4.4 years (interquartile range (IQR) 1.0–13.3). The etiology of DCM was idiopathic (66

Orthotopic heart transplantation (HT) is an option for end-stage heart failure in pediatric patients with a variety of diagnoses. However, posttransplant survival is limited by graft failure, which can occur at any point in time following transplantation. This chapter provides a comprehensive overview of the causes of graft failure in pediatric HT, as well as highlighting pathophysiology, evaluation, and management strategies.

Introduction: Monogenic causes of dilated cardiomyopathy (DCM) are commonly identified in children. While DCM frequently presents with symptomatic heart failure (HF), whether an identified genetic cause of DCM implies disease severity or eventual outcome in children is unclear. Goals/Aims: To assess whether clinical or phenotypic disease severity is different in children with an identifiable pathogenic or likely pathogenic (P/LP) variant in a cardiomyopathy gene, using a multi-institutional cohort of children with DCM, and to determine the association of these variants with disease outcomes. Methods: Children (0-18 yrs) from 14 pediatric centers in North America with an echo diagnosis of non-syndromal DCM were studied: phenotypic features included ancestry, family history, presentation age, severity of LV dilation, ejection fraction (EF), and clinical HF. A panel of 37 known cardiomyopathy-associated genes was interrogated by exome sequencing with targeted analysis for P/LP variants. Outcomes of death, cardiac transplant, and continuing LV dysfunction vs echo normalization were assessed prospectively. Results: Between 2012-2016, 279 DCM probands (47% male) were enrolled with a median (IQR) age at diagnosis of 1.6 (0.4-10.4) yrs. Median follow-up time was 1.1 (0.2-4.0) yrs, Gene variants designated as P/LP were identified in 18 of the 37 genes evaluated, with TTN (17%), TNNT2 (15%), MYH7 (15%), RBM20 (9%), and LMNA (8%) being the most frequently implicated genes. Only 19% of the overall cohort yielded an identifiable genetic cause, without any difference between ancestries. Children >12 yrs old had the highest genetic yield at 34% (p<0.05). Symptoms of HF occurred in 62% of pts at or within 12 months of presentation who carried P/LP genetic variant, but presentation HF symptoms, LVEF, or LV dilation were not associated with an identifiable genetic cause. The rate of death or cardiac transplant did not differ with P/LP variant presence or absence and exceeded 60% at 10 yrs after diagnosis. On competing risks analysis (Figures 1 and 2), a trend (p=0.09) towards greater echo normalization, reaching 25% vs 10%, was noted in P/LP variant-negative pts by 10 yrs after diagnosis. Conclusions: A genetic etiology was not associated with the phenotypic severity of DCM at diagnosis. Echo normalization of LV function over time was noted more frequently in patients who did not have an identified P/LP variant.

Importance:Studies suggest that everolimus may reduce the risk of rejection, cardiac allograft vasculopathy (CAV), chronic kidney disease (CKD), and cytomegalovirus (CMV) after heart transplant. Everolimus use is controversial because of data demonstrating higher infection deaths when everolimus is introduced de novo after transplant. It is unclear whether everolimus is safe and effective when initiated at 6 months posttransplant in children, a population in which median graft survival is limited to 15 years and randomized clinical trials are lacking. Objective:To evaluate the safety and efficacy of everolimus combined with low-dose tacrolimus to prevent major adverse transplant events (MATEs) in children after heart transplant. Design, Setting, and Participants:Multicenter, randomized, open-label, clinical trial enrolling 211 patients who were alive 6 months after pediatric heart transplant at 25 US sites from February 2018 to August 2020. The last date of follow-up was April 17, 2023. Interventions:Participants were randomized to receive everolimus and low-dose tacrolimus (n = 107) or standard-dose tacrolimus and mycophenolate mofetil (n = 104) for 30 months. Main Outcomes and Measures:The primary efficacy end point was the MATE-3 score at 30 months, a validated composite ordinal end point including acute cellular rejection, CAV, and CKD. The primary safety end point was the MATE-6 score, encompassing the MATE-3 score plus antibody-mediated rejection, infection, and posttransplant lymphoproliferative disorder. Results:Among 211 children randomized, the mean age was 8.2 (SD, 6.3) years, 97 (46%) underwent transplant for congenital heart disease, and 49 (23%) were treated for rejection before 6 months. At 30 months, the mean MATE-3 score did not differ between the 2 treatment groups (mean difference, -0.32; 95% CI, -0.90 to 0.20; P = .16). The mean MATE-6 score was no higher in the everolimus group than in the mycophenolate group (baseline-adjusted mean difference, -0.40; 95% CI, -1.81 to 0.93), meeting the success criterion for safety (noninferiority margin <3). There were no differences in graft survival, MATE-free survival, or freedom from any individual MATE. Everolimus was associated with greater improvement in estimated glomerular filtration rate at 12 months (mean difference, 10.5 mL/min/1.73 m2; 95% CI, 1.09-19.91 mL/min/1.73 m2) and a lower incidence of CMV infection (hazard ratio, 0.50; 95% CI, 0.26-0.93). Conclusions and Relevance:Among 6-month pediatric heart transplant survivors, everolimus and low-dose tacrolimus did not differ from tacrolimus and mycophenolate in preventing the composite of cellular rejection, CAV, and CKD at 30 months. However, everolimus and low-dose tacrolimus appear to be safe based on the total burden of 6 MATEs and may be associated with improved kidney function and less CMV infection. Trial Registration:ClinicalTrials.gov Identifier: NCT03386539.

Valsartan has been shown to attenuate phenotypic progression among individuals with early-stage sarcomeric hypertrophic cardiomyopathy (HCM). Myocardial tissue characterization by cardiac magnetic resonance (CMR) imaging may enhance mechanistic insights, but whether valsartan influences these parameters remains uncertain. To evaluate the treatment effects of valsartan on myocardial structure, function, and tissue parameters in early-stage sarcomeric HCM. This prespecified CMR substudy of the VANISH (Valsartan for Attenuating Disease Evolution in Early Sarcomeric Hypertrophic Cardiomyopathy) randomized clinical trial evaluated treatment effects of valsartan vs placebo on myocardial structure, function, and tissue parameters and was conducted from April 2014 through July 2019 at 17 international sites. Individuals aged 8 to 45 years with early-stage HCM aged between 8 and 45 years and with no or minimal symptoms were eligible for inclusion. Treatment with placebo or valsartan (80 mg per day for children weighing <35 kg, 160 mg per day for children weighing ≥35 kg, or 320 mg per day for adults aged 18 years or older). The primary outcome was mean change in CMR parameters between baseline and year 2, including indexed extracellular volume (iECV), indexed intracellular volume (iICV), and late gadolinium enhancement (LGE). Mean between-group differences in CMR parameters between baseline and year 2 were evaluated using multivariable mixed-effects linear regression models. Overall, 137 of 178 VANISH participants (77.0%) underwent CMR imaging at baseline and year 2. Among these participants, mean (SD) age was 23 (10) years, and 51 participants (37.2%) were female. Baseline characteristics and CMR parameters were well balanced between treatment groups. Higher LGE, iECV, and iICV at baseline were associated with higher cardiac biomarker levels and more pronounced cardiac remodeling. Between baseline and year 2, valsartan appeared to increase left ventricular (LV) end-diastolic volume index (mean difference [MD], 3.3 mL/m2; 95% CI, 0.4-6.2; P = .03), suggesting treatment benefit, but did not significantly impact LV mass index (MD, −2.9 g/m2; 95% CI, −6.1 to 0.2; P = .07) or LV ejection fraction. Similarly, valsartan appeared to reduce decline in right ventricular volumes. Valsartan appeared to significantly reduce iICV progression (MD, −5.0 mL/m2; 95% CI, −9.7 to −0.4; P = .03), but did not impact iECV (MD, 0.0 mL/m2; 95% CI, −1.4 to 1.3; P = .95) or LGE progression (MD, 0.5%; 95% CI, −0.4 to 1.3; P = .30). These findings enhance mechanistic insights into the effect of valsartan in early-stage HCM, showing potential benefits on biventricular remodeling and myocardial intracellular volume. Further research to identify cellular mechanisms of valsartan on HCM progression is needed. ClinicalTrials.gov Identifier: NCT01912534

Background: Children with dilated cardiomyopathy (DCM) are at high risk for morbidity and death. There are few data on the utility of biomarkers in this population. Research Question/Hypothesis: We aimed to evaluate a panel of cardiac biomarkers as predictors of death or heart transplant within 2 years of diagnosis. Methods: Patients <21 years of age at DCM diagnosis were enrolled at 15 North American pediatric cardiomyopathy centers within one year of diagnosis with collection of serum, echocardiographic and clinical data at enrollment. Results: Data from 74 subjects were analyzed, median age 2.1 years at enrollment [interquartile range (IQR 0.7-12.8)], 40 (54%) female, and 56 (76%) enrolled within 90 days of diagnosis. The primary endpoint of death or heart transplant was met in 13 subjects (18%). Several cardiac biomarkers of heart failure (HF), N-terminal pro B-type natriuretic peptide, growth differentiation factor-15, interleukin-6, and C-reactive protein were associated with the primary endpoint (p <0.05 for all) in the univariate analysis. In multivariable analysis, growth differentiation factor-15 was independently associated with the primary endpoint (hazard ratio 5.23, 95% confidence interval 2.20, 12.44; p <0.001). Conclusion: Growth differentiation factor-15, an emerging circulating biomarker for HF, was independently associated with death or heart transplantation within 2 years in children with a recent diagnosis of DCM. Traditional biomarkers such as NT pro-BNP were found to be less predictive on single point assessment. If validated in further studies, this biomarker could serve as an endpoint for prospective clinical trials.

Background Pediatric dilated cardiomyopathy often leads to death or cardiac transplantation. We sought to determine whether changes in left ventricular (LV) end‐diastolic dimension (LVEDD), LV end‐diastolic posterior wall thickness, and LV fractional shortening (LVFS) over time may help predict adverse outcomes. Methods and Results We studied children up to 18 years old with dilated cardiomyopathy, enrolled between 1990 and 2009 in the Pediatric Cardiomyopathy Registry. Changes in LVFS, LVEDD, LV end‐diastolic posterior wall thickness, and the LV end‐diastolic posterior wall thickness:LVEDD ratio between baseline and follow‐up echocardiograms acquired ≈1 year after diagnosis were determined for children who, at the 1‐year follow‐up had died, received a heart transplant, or were alive and transplant‐free. Within 1 year after diagnosis, 40 (5.0%) of the 794 eligible children had died, 117 (14.7%) had undergone cardiac transplantation, and 585 (73.7%) had survived without transplantation. At diagnosis, survivors had higher median LVFS and lower median LVEDD Z scores. Median LVFS and LVEDD Z scores improved among survivors (Z score changes of +2.6 and −1.1, respectively) but remained stable or worsened in the other 2 groups. The LV end‐diastolic posterior wall thickness:LVEDD ratio increased in survivors only, suggesting beneficial reverse LV remodeling. The risk for death or cardiac transplantation up to 7 years later was lower when LVFS was improved at 1 year (hazard ratio [HR], 0.83; P=0.004) but was higher in those with progressive LV dilation (HR, 1.45; P<0.001). Conclusions Progressive deterioration in LV contractile function and increasing LV dilation are associated with both early and continuing mortality in children with dilated cardiomyopathy. Serial echocardiographic monitoring of these children is therefore indicated. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT00005391.

BACKGROUND:Extending survival after heart transplant (HT) is of paramount importance for childhood recipients of HT. Acute rejection is a significant event, and biopsy remains the most specific means for distinguishing between cellular (ACR) and antibody-mediated rejection (AMR). METHODS:All children in the Pediatric Heart Transplant Society Registry who underwent HT between January 2015 and June 2022 and had ≥1 rejection episode were included. Survival was compared between AMR and ACR-only. Secondary outcomes of infection, malignancy, and cardiac allograft vasculopathy (CAV) were assessed. Risk factors for graft loss after AMR were identified using Cox proportional hazard modeling. RESULTS:Among 906 children with rejection, 697 (77%) with complete biopsy information were included. AMR was present on biopsy in 261 (37%) patients; ACR-only was present in 436 (63%). Time to rejection was earlier for AMR, median time from HT to rejection 0.11 versus 0.29 years, p = 0.0006. Survival after AMR in the 1st year was lower than survival after ACR-only. Predictors of graft loss after AMR were younger age at HT, congenital heart disease, and rejection with hemodynamic compromise. There was no difference in time to CAV, infection, or malignancy after rejection between groups. CONCLUSIONS:The largest analysis of pediatric HT rejection with biopsy data to identify AMR underscores the continued importance of AMR on survival. AMR is associated with higher graft loss versus ACR when occurring in the first-year post-HT. Predictors of graft loss after AMR identify patients who may benefit from increased surveillance or augmented maintenance immunosuppression.

ImportanceValsartan has shown promise in attenuating cardiac remodeling in patients with early-stage sarcomeric hypertrophic cardiomyopathy (HCM). Genetic testing can identify individuals at risk of HCM in a subclinical stage who could benefit from therapies that prevent disease progression.ObjectiveTo explore the potential for valsartan to modify disease development, and to characterize short-term phenotypic progression in subclinical HCM.Design, Setting, and ParticipantsThe multicenter, double-blind, placebo-controlled Valsartan for Attenuating Disease Evolution in Early Sarcomeric Hypertrophic Cardiomyopathy (VANISH) randomized clinical trial was conducted from April 2014 to July 2019 at 17 sites in 4 countries (Brazil, Canada, Denmark, and the US), with 2 years of follow-up. The prespecified exploratory VANISH cohort studied here included sarcomere variant carriers with subclinical HCM and early phenotypic manifestations (reduced E′ velocity, electrocardiographic abnormalities, or an increased left ventricular [LV] wall thickness [LVWT] to cavity diameter ratio) but no LV hypertrophy (LVH). Data were analyzed between March and December 2022.InterventionsTreatment with placebo or valsartan (80 mg/d for children weighing <35 kg, 160 mg/d for children weighing ≥35 kg, or 320 mg/d for adults aged ≥18 years).Main Outcomes and MeasuresThe primary outcome was a composite z score incorporating changes in 9 parameters of cardiac remodeling (LV cavity volume, LVWT, and LV mass; left atrial [LA] volume; E′ velocity and S′ velocity; and serum troponin and N-terminal prohormone of brain natriuretic peptide levels).ResultsThis study included 34 participants, with a mean (SD) age of 16 (5) years (all were White). A total of 18 participants (8 female [44%] and 10 male [56%]) were randomized to valsartan and 16 (9 female [56%] and 7 male [44%]) were randomized to placebo. No statistically significant effects of valsartan on cardiac remodeling were detected (mean change in composite z score compared with placebo: −0.01 [95% CI, −0.29 to 0.26]; P = .92). Overall, 2-year phenotypic progression was modest, with only a mild increase in LA volume detected (increased by 3.5 mL/m2 [95% CI, 1.4-6.0 mL/m2]; P = .002). Nine participants (26%) had increased LVWT, including 6 (18%) who developed clinically overt HCM. Baseline LA volume index (LAVI; 35 vs 28 mL/m2; P = .01) and average interventricular septum thickness (8.5 vs 7.0 mm; P = .009) were higher in participants who developed HCM.Conclusions and RelevanceIn this exploratory cohort, valsartan was not proven to slow progression of subclinical HCM. Minimal changes in markers of cardiac remodeling were observed, although nearly one-fifth of patients developed clinically overt HCM. Transition to disease was associated with greater baseline interventricular septum thickness and LAVI. These findings highlight the importance of following sarcomere variant carriers longitudinally and the critical need to improve understanding of factors that drive disease penetrance and progression.Trial RegistrationClinicalTrials.gov Identifier: NCT01912534

Background Myocardial fibrosis, as diagnosed on cardiac magnetic resonance imaging (cMRI) by late gadolinium enhancement (LGE), is associated with adverse outcomes in adults with hypertrophic cardiomyopathy (HCM), but its prevalence and magnitude in children with HCM have not been established. We investigated: (1) the prevalence and extent of myocardial fibrosis as detected by LGE cMRI; (2) the agreement between echocardiographic and cMRI measurements of cardiac structure; and (3) whether serum concentrations of N-terminal pro hormone B-type natriuretic peptide (NT-proBNP) and cardiac troponin-T are associated with cMRI measurements. Methods A cross-section of children with HCM from 9 tertiary-care pediatric heart centers in the U.S. and Canada were enrolled in this prospective NHLBI study of cardiac biomarkers in pediatric cardiomyopathy (ClinicalTrials.gov Identifier: NCT01873976). The median age of the 67 participants was 13.8 years (range 1-18 years). Core laboratories analyzed echocardiographic and cMRI measurements, and serum biomarker concentrations. Results In 52 children with non-obstructive HCM undergoing cMRI, overall low levels of myocardial fibrosis with LGE > 2% of left ventricular (LV) mass were detected in 37 (71%) (median %LGE, 9.0%; IQR: 6.0%, 13.0%; range, 0% to 57%). Echocardiographic and cMRI measurements of LV dimensions, LV mass, and interventricular septal thickness showed good agreement using the Bland-Altman method. NT-proBNP concentrations were strongly and positively associated with LV mass and interventricular septal thickness ( P < .001), but not LGE. Conclusions Low levels of myocardial fibrosis are common in pediatric patients with HCM seen at referral centers. Longitudinal studies of myocardial fibrosis and serum biomarkers are warranted to determine their predictive value for adverse outcomes in pediatric patients with HCM. (Am Heart J 2023;264:153-162.)

Background: Antibody-mediated rejection (AMR) is of great relevance when assessing therapies to improve survival for pediatric heart transplant (HT). Biopsy (EMB) is the most specific means for diagnosing AMR. This study explores the impact on survival and adverse events after treated rejection (TRej) in children with AMR on EMB (any pAMR 1h or i, 2, or 3) vs acute cellular rejection (ACR). Methods: Children in the Pediatric HT Study transplanted between 1/2015-6/2022 who survived ≥2 weeks and had at least 1 TRej with EMB data were included. Survival was compared after 1st TRej with any AMR to pure ACR. Secondary outcomes of infection, malignancy, and cardiac allograft vasculopathy (CAV) after 1st TRej were assessed. Risk factors for mortality after AMR were identified using Cox proportional hazard modeling. Results: Among 3172 HT recipients, 906 (29%) had at least 1 TRej. Of these, 697 (77%) had EMB data to determine the presence of AMR. At the 1st TRej episode, 261 (37%) children had features of AMR. Median time to 1st Trej was earlier in those with AMR vs ACR, 0.11 vs 0.29 yrs. p=0.001. Survival after 1st TRej with AMR was worse than ACR in the 1st yr post HT (A); however, survival was similar when 1st TRej occurred after year 1 (B) (Figure 1 A, B). The AMR group had higher panel reactive antibody at HT, more congenital heart disease (CHD), and more had ABO incompatible HT (all p<0.05). There was no difference in time to 1st infection, malignancy, or CAV between those with treated AMR vs ACR. Multivariate predictors of graft loss after AMR were younger age, CHD, and ECMO at HT, and hemodynamic compromise at TRej (all p<0.048). Neither AMR grade nor concomitant ACR was associated with graft loss after AMR. Conclusion: This is the largest analysis of contemporary outcomes of EMB-confirmed AMR in pediatric HT. Findings underscore the impact of early AMR on graft loss and the need for tailored therapies. Similar time to infection after AMR vs ACR is notable since immune targets of therapy often differ.

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.

BackgroundDespite ubiquitous exposure to sensitizing events, most Fontan PLE patients have low panel reactive antibodies (PRA). To assess whether they are at risk for donor-specific antibody (DSA) memory response following heart transplantation (HT) when their PLE resolves, DSA profiles, incidence of rejection, and graft outcomes in Fontan recipients with and without PLE were compared. MethodsPatient characteristics, appearance of newly detected DSA (nDSA), and graft outcomes were compared between patients with and without PLE using Wilcoxon rank-sum and Chi-squared tests. DSA burden was quantified using titers and time to nDSA, incidence of rejection, and graft outcomes were compared using Kaplan-Meier curves and the log-rank test. ResultsCharacteristics of patients with and without PLE were similar. Lymphocyte and albumin levels were lower in the PLE group, and flow PRA were comparable. Graft failure, CAV, and ACR were similar between the two groups, but AMR occurred more frequently in the PLE group (p = .03). Nearly 50% of PLE patients experienced class II nDSA by 1-year post-HT, compared to 30% of non-PLE patients, but this difference was statistically not significant. Antibody burden did not differ between groups. ConclusionsIn this cohort, PLE was associated with AMR within the first-year post-HT, despite no significant difference in nDSA. Small patient numbers limited statistical comparison of nDSA in this cohort. PLE may be a risk factor for AMR post-HT, and the possibility of a clinically important DSA memory response remains. Larger studies are necessary to better understand these preliminary findings.

Objectives: Donor-specific cell-free DNA shows promise as a noninvasive marker for allograft rejection, but as yet has not been validated in both adult and pediatric recipients. The study objective was to validate donor fraction cell- free DNA as a noninvasive test to assess for risk of acute cellular rejection and antibodymediated rejection after heart transplantation in pediatric and adult recipients. Methods: Pediatric and adult heart transplant recipients were enrolled from 7 participating sites and followed for 12 months or more with plasma samples collected immediately before all endomyocardial biopsies. Donor fraction cellfree DNA was extracted, and quantitative genotyping was performed. Blinded donor fraction cell-free DNA and clinical data were analyzed and compared with a previously determined threshold of 0.14%. Sensitivity, specificity, negative predictive value, positive predictive value, and receiver operating characteristic curves were calculated. Results: A total of 987 samples from 144 subjects were collected. After applying predefined clinical and technical exclusions, 745 samples from 130 subjects produced 54 rejection samples associated with the composite outcome of acute cellular rejection grade 2R or greater and pathologic antibody- mediated rejection 2 or greater and 323 healthy samples. For all participants, donor fraction cell-free DNA at a threshold of 0.14% had a sensitivity of 67%, a specificity of 79%, a positive predictive value of 34%, and a negative predictive value of 94% with an area under the curve of 0.78 for detecting rejection. When analyzed independently, these results held true for both pediatric and adult cohorts at the same threshold of 0.14% (negative predictive value 92% and 95%, respectively). Conclusions: Donor fraction cell-free DNA at a threshold of 0.14% can be used to assess for risk of rejection after heart transplantation in both pediatric and adult patients with excellent negative predictive value. (J Thorac Cardiovasc Surg 2023;165:460-8)

Purpose The TEAMMATE Trial is studying everolimus (EVL) with low-dose tacrolimus (LDTAC) vs. standard tacrolimus (TAC) with mycophenolate (MMF) in a randomized trial in children enrolled at 6 months post-heart transplant. Since therapeutic levels are correlated with lower rejection rates, we sought to describe the immunosuppressant drug level monitoring experience in the trial to date. Methods All children in the TEAMMATE Trial remaining on assigned therapy as of August 2021 were included. Drug levels were obtained at 0, 3, 6, 9, 12, 18, 24, & 30 months post-randomization. Formulation, time to therapeutic level, and number of dose adjustments were tracked at each study visit. Stability was assessed by the coefficient of variation (CoV) (SD/mean). Adherence was assessed by the % of levels within range; and the SD of levels divided by therapeutic window (lower values indicating better adherence). Independence of all levels was assumed in analysis. Results A total of 211 children were randomized to either EVL/LDTAC (n=107) or usual care TAC/MMF (n=104). After randomization, a therapeutic level was achieved in 94% (EVL) & 91% (MMF). Liquid formulation was used in 37% of EVL subjects. Median time to a therapeutic level for EVL was 10 (tablet) & 11 (liquid) days. The CoV was lower for TAC (36%), EVL (47%), & LDTAC (52%), compared to MMF (103%). Drug levels were in target range 80% (EVL), 20% (MMF), 55% (LDTAC), & 54% (TAC) of the time (Figure). The SD of levels divided by therapeutic window was lowest for EVL (44%), compared to TAC (94%), LDTAC (112%), & MMF (158%). In response to these levels, dose changes were made in 13% (EVL) & 18% (LDTAC) in the EVL/LDTAC group (16% combined) and in 27% (TAC) and 11% (MMF) in the control group (22% combined). Conclusion EVL achieves stable target levels more frequently than MMF, LDTAC or TAC, likely due to decreased trough level variability and its wider therapeutic window. Fewer dose adjustments have been required for the EVL/LDTAC regimen compared to TAC/MMF. The TEAMMATE Trial is studying everolimus (EVL) with low-dose tacrolimus (LDTAC) vs. standard tacrolimus (TAC) with mycophenolate (MMF) in a randomized trial in children enrolled at 6 months post-heart transplant. Since therapeutic levels are correlated with lower rejection rates, we sought to describe the immunosuppressant drug level monitoring experience in the trial to date. All children in the TEAMMATE Trial remaining on assigned therapy as of August 2021 were included. Drug levels were obtained at 0, 3, 6, 9, 12, 18, 24, & 30 months post-randomization. Formulation, time to therapeutic level, and number of dose adjustments were tracked at each study visit. Stability was assessed by the coefficient of variation (CoV) (SD/mean). Adherence was assessed by the % of levels within range; and the SD of levels divided by therapeutic window (lower values indicating better adherence). Independence of all levels was assumed in analysis. A total of 211 children were randomized to either EVL/LDTAC (n=107) or usual care TAC/MMF (n=104). After randomization, a therapeutic level was achieved in 94% (EVL) & 91% (MMF). Liquid formulation was used in 37% of EVL subjects. Median time to a therapeutic level for EVL was 10 (tablet) & 11 (liquid) days. The CoV was lower for TAC (36%), EVL (47%), & LDTAC (52%), compared to MMF (103%). Drug levels were in target range 80% (EVL), 20% (MMF), 55% (LDTAC), & 54% (TAC) of the time (Figure). The SD of levels divided by therapeutic window was lowest for EVL (44%), compared to TAC (94%), LDTAC (112%), & MMF (158%). In response to these levels, dose changes were made in 13% (EVL) & 18% (LDTAC) in the EVL/LDTAC group (16% combined) and in 27% (TAC) and 11% (MMF) in the control group (22% combined). EVL achieves stable target levels more frequently than MMF, LDTAC or TAC, likely due to decreased trough level variability and its wider therapeutic window. Fewer dose adjustments have been required for the EVL/LDTAC regimen compared to TAC/MMF.

To understand the genetic contribution to primary pediatric cardiomyopathy, we performed exome sequencing in a large cohort of 528 children with cardiomyopathy. Using clinical interpretation guidelines and targeting genes implicated in cardiomyopathy, we identified a genetic cause in 32% of affected individuals. Cardiomyopathy sub-phenotypes differed by ancestry, age at diagnosis, and family history. Infants < 1 year were less likely to have a molecular diagnosis (p < 0.001). Using a discovery set of 1,703 candidate genes and informatic tools, we identified rare and damaging variants in 56% of affected individuals. We see an excess burden of damaging variants in affected individuals as compared to two independent control sets, 1000 Genomes Project (p < 0.001) and SPARK parental controls (p < 1 × 10-16). Cardiomyopathy variant burden remained enriched when stratified by ancestry, variant type, and sub-phenotype, emphasizing the importance of understanding the contribution of these factors to genetic architecture. Enrichment in this discovery candidate gene set suggests multigenic mechanisms underlie sub-phenotype-specific causes and presentations of cardiomyopathy. These results identify important information about the genetic architecture of pediatric cardiomyopathy and support recommendations for clinical genetic testing in children while illustrating differences in genetic architecture by age, ancestry, and sub-phenotype and providing rationale for larger studies to investigate multigenic contributions.

BACKGROUND: Reports focused on adult heart transplant (HTx) recipients with COVID-19 suggest an increased risk of severe disease, however; it is unclear if this holds true for pediatric HTx patients, given the typically milder course of illness in children in general with COVID-19. We sought to rapidly implement a system for multi-center data collection on pediatric HTx candidates and recipients, with the aim of describing the patient population and infection related outcomes. METHODS: The Pediatric Heart Transplant Society (PHTS) is a multi-center collaboration that seeks to improve the outcomes of children who are listed and undergo HTx. The society consists of pediatric HTx centers in North America (n = 53), UK (n = 2), and Brazil (n = 1). In response to the pandemic, PHTS developed a web-based platform to collect COVID-19 specific data on pediatric HTx candidates and recipients. Non-PHTS centers were also invited to submit data. Data fields included pre-and postHTx patient characteristics, presumed versus documented infection, need for hospitalization (including ICU and ventilator use), treatments administered, and 30-day outcome (resolution, death, sequelae, and or unresolved) RESULTS: Data collection was initiated on 4/30/20. As of 03/15/21 there were 225 patients [19 pre-HTx and 206 post-HTx, median age 14 years (IQR 7, 18)] reported from 41 centers. Hospitalization occurred in 42% (n = 8) of the pre-HTx and 21% (n=43) of the post-HTx patients. Among the patients listed for HTx, 21% (n = 4) required ICU and 10.5% (n = 2) were mechanically ventilated. Among post-HTx patients, 7% (n = 14) required ICU and 1% (n = 3) were mechanically ventilated. At 30 days, the majority of patients had resolution of symptoms (94.7% pre-HTx, 95.6% post-HTx). One death was reported in a post-HTx patient prior to 30 days from onset of COVID-19 illness. CONCLUSIONS: These data demonstrate the ability to rapidly adapt the PHTS data collection infrastructure in response to a novel infection and represent the first known multi-center report of characteristics and early outcomes for patients listed and following pediatric HTx with COVID-19. Hospitalization appears to be more common for both candidates and recipients due to COVID-19 than for the general pediatric population though stays were short and mortality minimal.

Background Obesity and dyslipidemia afflict children of all ages. We explored the prevalence of obesity and dyslipidemia in pediatric heart transplant (HT) recipients and its effects on cardiac allograft vasculopathy (CAV) and survival. Methods This study included primary HT recipients (<= 18 years) transplanted between 01/1996 and 12/2018 included in the Pediatric Heart Transplant Society database. Obesity was categorized according to WHO/CDC guidelines and dyslipidemia according to the National Cholesterol Education Program. Kaplan-Meier analyses for CAV and graft loss stratified for BMI and lipid panels were generated and risk factors identified using multivariate analyses. Results Among 6291 HT patients (median age [range] at HT = 4.3 [0.6-12.8] years; 45% Female; 68% White), 56% had a normal BMI at HT. Obese patients at HT had an increased risk for graft loss (HR 1.19, 95% CI 1.01-1.4, p = .04). Poor total cholesterol (TC), LDL-C, and TG were associated with the risk of both CAV (HR 1.79, p < .0001; HR 1.65, p = .0015; HR 1.53, p < .0001, respectively) and graft loss (HR 1.58, p = .0008; HR 1.22, p = .04; HR 1.43, p = .0007, respectively). Conclusions Pediatric patients who are obese at the time of HT and dyslipidemic at 1 year post-HT are at an increased risk for CAV and graft loss. Preventative interventions may reduce morbidity and mortality among this cohort.

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.