Progressive Left Ventricular Remodeling for Predicting Mortality in Children With Dilated Cardiomyopathy: The Pediatric Cardiomyopathy Registry.

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.

Contemporary outcomes of pediatric cardiac transplantation with a positive retrospective crossmatch.

BACKGROUND: A positive crossmatch (+ XM) has traditionally been associated with adverse outcomes following pediatric heart transplantation. However, more recent studies suggest that favorable intermediate-term outcomes may be achieved despite a + XM. This study's hypothesis is that children with a + XM have similar long-term survival, but higher rate of complications such as rejection, coronary allograft vasculopathy (CAV), and infection, compared to patients with a negative (-) XM. METHODS: The Pediatric Heart Transplant Society Registry (PHTS) database was queried from 2010-2021 for all patients <18 years of age with a known XM. Baseline demographics were compared between + XM and - XM groups using appropriate parametric and non-parametric group comparisons. Cox Proportional Hazards Modeling was used to identify risk factors for post-transplant graft loss, rejection, and CAV. RESULTS: Of 4599 pediatric heart transplants during the study period, XM results were available for 3914 (85%), of which 373 (9.5%) had a + XM. Univariate analysis showed lower 10-year survival for patients with + XM (HR = 1.3, p = .04). Multivariate analyses revealed no significant difference in 10-year survival in the 2 groups; however, time to first rejection (p = .0001) remained significantly shorter in the + XM group. CONCLUSIONS: Pediatric patients transplanted across a + XM experience earlier rejection; however, after multivariate adjustment, + XM is not independently associated with intermediate-term graft loss. The risk of heart transplantation against a + XM must be balanced with the ongoing risk of waitlist mortality.

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.

Single-drug immunosuppression is associated with noninferior medium-term survival in pediatric heart transplant recipients.

BACKGROUND: Patients are usually maintained on at least 2 immunosuppressive drugs (ISDs) after the first year post heart transplant. Anecdotally, some children are switched to single-drug monotherapy (a single ISD) for various reasons and varying durations. Outcomes associated with differences in immunosuppression after heart transplantation are unknown for children. OBJECTIVES: A priori we defined a noninferiority hypothesis for monotherapy compared to ≥2 ISDs. The primary outcome was graft failure, a composite of death and retransplantation. Secondary outcomes included rejection, infection, malignancy, cardiac allograft vasculopathy and dialysis. METHODS: This international, multicenter, retrospective, observational cohort study used data from the Pediatric Heart Transplant Society. We included patients who underwent first-time heart transplant <18 years of age between 1999 and 2020 with ≥1 year of follow-up data available. RESULTS: Our analysis included 3493 patients with a median time post-transplant of 6.7 years. There were 893 patients (25.6%) switched to monotherapy at least once with the remaining 2600 patients always on ≥2 ISDs. The median time on monotherapy after the first year post-transplant was 2.8 years (range 1.1-5.9 years). We found an adjusted hazard ratio (HR) of 0.65 (95%CI: 0.47-0.88) favoring monotherapy compared to ≥2 ISDs (p = 0.002). There were no meaningful differences in the incidence of secondary outcomes between groups, except for a lower rate of cardiac allograft vasculopathy in patients on monotherapy (HR 0.58, 95%CI: 0.45-0.74). CONCLUSIONS: For pediatric heart transplant recipients placed on monotherapy, immunosuppression with a single ISD after the first year post-transplant was noninferior to standard therapy with ≥2 ISDs in the medium term. CONDENSED ABSTRACT: Some children are switched to a single immunosuppressive drug (ISD) for various reasons after heart transplant, but outcomes associated with differences in immunosuppression are unknown for children. We assessed graft failure in children on a single ISD (monotherapy) compared to ≥2 ISDs in a cohort of 3493 children with a first heart transplant. We found an adjusted hazard ratio of 0.65 (95%CI: 0.47-0.88) favoring monotherapy. We concluded that for pediatric heart transplant recipients placed on monotherapy, immunosuppression with a single ISD after the first year post-transplant was non-inferior to standard therapy with ≥2 ISDs in the medium term.

Masked Hypertension in Pediatric Heart Transplant Recipients.

BACKGROUND: Masked hypertension (HTN), especially, isolated nocturnal HTN (INH) has been shown to be a risk factor for cardiovascular disease (CVD) but is not studied well in pediatric heart transplant (PHT) patients. Ambulatory blood pressure monitoring (ABPM) is known to identify patients with HTN but is not used routinely in PHT. METHODS: A single-center, prospective, cross-sectional study of PHT recipients was performed to observe the incidence of masked HTN using 24-h ABPM. The relationship between ABPM parameters and clinical variables was assessed using Spearman correlation coefficient. p value < 0.05 was considered significant. RESULTS: ABPM was performed in 34 patients, mean age 14 ± 5 years, median 5.5 years post-PHT. All patients had normal cardiac function, left ventricular mass index and blood pressure measurements in the clinic. Four patients had known prior HTN and on medications, one of them was uncontrolled. Of the remaining 30 patients, 18 new patients were diagnosed with masked HTN, of which 14 had INH. Diurnal variation was abnormal in 82% (28/34) patients. 24-h diastolic blood pressure (DBP) index correlated with glomerular filtration rate (GFR) (r = - 0.44, p = 0.01). There was no correlation between other ABPM parameters with tacrolimus trough levels. CONCLUSIONS: ABPM identified masked HTN in 60% of patients, with majority being INH. Abnormal circadian BP patterns were present in 82% and an association was found between GFR and DBP parameters. HTN, especially INH, is under-recognized in PHT recipients and ABPM has a role in their long-term care.

Waitlist and Posttransplant Outcomes of Children and Young Adults With Hypertrophic Cardiomyopathy.

BACKGROUND: Heart transplantation (HT) is standard therapy for end-stage hypertrophic cardiomyopathy (HCM); however, few studies have described outcomes of older children and young adults with HCM listed for HT. Our objective was to compare waitlist and post-HT outcomes among pediatric and young adult patients with HCM and dilated cardiomyopathy (DCM). METHODS: The Scientific Registry of Transplant Recipients was queried for patients with HCM and DCM listed at ≤25 years of age. Patient characteristics, waitlist and post-HT survival were compared between younger (≤5 years of age) and older (>5 to ≤25 years of age) HCM patients and between HCM and DCM patients. RESULTS: Among 6252 patients listed for HT at ≤25 years of age with DCM and HCM, 3926 and 250 were in the older cohort and 1944 and 132 were in the younger cohort, respectively. Older HCM patients were less likely to be critically ill at listing compared with younger HCM patients (P = .0001). Waitlist mortality was similar between HCM and DCM patients in both age cohorts. Post-HT survival in HCM patients was similar between the age cohorts. In the younger cohort, early post-HT survival was worse in HCM compared with DCM (P = .009), with no difference in long-term survival. Survival was similar between the older cohorts. CONCLUSIONS: Older children and young adults with HCM are less critically ill than the younger cohort and show waitlist and post-HT survival similar to DCM patients. The young children with HCM had worse early posttransplantation survival, though long-term survival was same as DCM.

COVID-19 infection in pediatric solid organ transplant patients.

BACKGROUND: Adult SOT recipients with COVID-19 have higher mortality rates when compared to general population. There is paucity of data on outcomes in pediatric SOT recipients. METHODS: This is a cross-sectional study investigating the prevalence of COVID-19 infection and outcomes in pediatric SOT (heart, liver, and kidney) recipients. We extracted demographic and clinical characteristics and COVID-19 testing (PCR or [Ab] test) results from medical records. Clinical characteristics were compared between patients who were positive for COVID-19 (PCR or Ab) and those who did not, using Mann-Whitney, Student's t test, or chi-square test. p value <.05 was statistically significant. RESULTS: A total of 108 SOT recipients with a median age of 13.1 (8.4, 17.8) years and median 4.2 (2.7, 7.9) years from transplant were checked for COVID-19 via a PCR or Ab test. A positive PCR was confirmed in 10 patients (9.3%), while 12 patients (11.1%) were positive for COVID-19 Ab. The patients who tested positive in our cohort were 9/50 (18%) heart, 6/68 (8.8%) kidney, and 7/50 (14%) liver transplant recipients. There were no differences in the clinical characteristics between patients with and without COVID-19 infection. All patients were either asymptomatic (50%) or had self-limiting symptoms. No changes were made to the immunosuppressive regimen. Only one patient was hospitalized and none had an oxygen requirement. CONCLUSIONS: In our cohort of pediatric SOT recipients, COVID-19 infection was asymptomatic or mild. This data may aid clinicians in counseling patients and families in this increased-risk population.

Cardiac Abnormalities Seen in Pediatric Patients During the SARS-CoV2 Pandemic: An International Experience.

Background During the SARS-CoV2 pandemic, there has been increase in hyperinflammatory presentation in previously healthy children with a variety of cardiac manifestations. Our objective is to describe the cardiac manifestations found in an international cohort of 55 pediatric cases with multi-system inflammatory syndrome (MIS-C) during the SARS-CoV2 pandemic. Methods and Results We reviewed data on previously healthy pediatric patients (≤18 years) with structurally normal hearts who presented at hospitals in the United States, United Kingdom, Spain and Pakistan with MIS-C and had consultation with a pediatric cardiologist. Data collected included demographics, clinical presentation, laboratory values, electrocardiographic abnormalities, echocardiographic findings and initial therapies. A total of 55 patients presented with MIS-C. Thirty-five patients (64%) had evidence of decreased left ventricular function, 17 (31%) had valvulitis, 12 (22%) with pericardial effusion and 11 (20%) with coronary abnormalities. Twenty-seven (49%) required ICU admission and 24 (44%) had evidence of shock. Eleven patients (20%) fulfilled complete Kawasaki disease criteria and had lower NT pro-BNP, D-dimer and ferritin levels compared with those who did not fulfill criteria. Electrophysiologic abnormalities occurred in 6 patients and included complete atrioventricular (AV) block, transient AV block and ventricular tachycardia. Conclusions We describe the first international cohort of pediatric patients with MIS-C during the SARS-CoV2 pandemic with a range of cardiac manifestations. This paper brings awareness and alertness to the global medical community to recognize these children during the pandemic and understand the need for early cardiology evaluation and follow-up.

Surveillance for cardiac allograft vasculopathy: Practice variations among 50 pediatric heart transplant centers.

BACKGROUND: Coronary allograft vasculopathy (CAV) is a leading cause of mortality after heart transplantation (HT) in children. Variation in CAV screening practices may impact detection rates and patient outcomes. METHODS: Among 50 Pediatric Heart Transplant Society (PHTS) sites from 2001 to 2016, coronary evaluations were classified as angiography or non-invasive testing, and angiograms were designated as routine or symptom based. CAV detection rates stratified by routine vs symptom-based angiograms were calculated. Freedom from CAV and mortality after CAV diagnosis, stratified by study indication, were calculated. RESULTS: A total of 3,442 children had 13,768 coronary evaluations; of these, 97% (n = 13,012) were for routine surveillance, and only 3% (n = 333) were for cause. Over the study period, CAV was detected in 472 patients (14%). Whereas 58% (n = 29) of PHTS sites evaluate by angiography alone, 42% reported supplementing with a non-invasive test, although only 423 non-invasive studies were reported. Angiographic detection of CAV was higher for symptom-based testing than for routine testing (29% vs 4%, p < 0.0001), although routine testing identified a majority of cases (88%; n = 414). The 10-year freedom from CAV was 77% overall. Once CAV is detected, 5-year graft survival was 58%, with lower survival for patients diagnosed after symptoms angiogram than after routine angiogram (30% vs 62%; p < 0.0001). CONCLUSIONS: Development of a robust model for CAV risk should allow low-risk patients to undergo less frequent invasive angiography without adverse impact on CAV detection rates or outcomes.

Safety of Enalapril in Infants: Data from the Pediatric Heart Network Infant Single Ventricle Trial.

OBJECTIVE: To assess the safety profile of angiotensin-converting enzyme inhibitor therapy in infants with single ventricle. STUDY DESIGN: The Pediatric Heart Network conducted a double-blind trial involving infants with single ventricle physiology randomized to receive enalapril or placebo and followed to 14 months of age. Data including demographics, drug administration, hemodynamic monitoring, laboratory measurements, adverse events, and survival were extracted from the public use data set and compared between the placebo and enalapril-treated groups. RESULTS: The Infant Single Ventricle trial randomized 230 patients, with 115 patients in each group. Initial enalapril dose was 0.10 mg/kg/d and median maximal dose was 0.38 mg/kg/d. There was no significant difference in change in blood pressure at study drug initiation or when resuming study drug after Glenn surgery. The incidence of hyperkalemia and neutropenia did not differ between groups. Renal dysfunction occurred in 3% of the enalapril group and none of the placebo patients, which was not statistically significant. There was a high frequency of serious adverse events in both groups. There was no difference in the frequency of heart transplant or death between groups. CONCLUSIONS: Enalapril did not have sustained hemodynamic effects at initiation or up-titration of drug. Creatinine and potassium were not different between groups, although renal dysfunction occurred more often in the patients on enalapril. Although efficacy of enalapril in neonates with single ventricle has not been demonstrated, the safety profile of angiotensin-converting enzyme inhibitors appears to be low risk in infants and children with significant heart disease.

Persistent hypogammaglobulinemia in pediatric solid organ transplant recipients.

INTRODUCTION: Hypogammaglobulinemia has not been well studied in pediatric solid organ transplant (SOT) recipients. We evaluated plasma immunoglobulin (Ig) and lymphocyte phenotypes among 31 pediatric heart and kidney recipients for two years post-transplant and from 10 non-transplanted children. METHODS: Plasma IgM, IgG, and IgA were quantified by immunoturbidimetric assays, IgG subclasses were quantified by bead-based multiplex immunoassay, and lymphocyte phenotypes were assessed by flow cytometry. RESULTS: Median age at transplant for SOT recipients was similar to that of the control cohort (15 vs. 12.5 years, respectively; P = .61). Mean plasma IgG and IgM levels for SOT recipients fell significantly below the control cohort means by 1 month post-transplant (P < .001 for both) and remained lower than control levels at 12-18 months post-transplant. Heart recipients had lower frequencies of a CD4+ naïve T lymphocytes relative to kidney recipients. CONCLUSIONS: Hypogammaglobulinemia was prevalent and persistent among pediatric SOT recipients and may be secondary to immunosuppressive medications, as well as loss of thymus tissue and CD45RA+   CD4+ T cells in heart recipients. Limitations of our study include but are not limited to small sample size from a single center, lack of samples for all participants at every time point, and lack of peripheral blood mononuclear cell samples for the non-transplanted cohort.

Right heart failure with left ventricular assist device implantation in children: An analysis of the Pedimacs registry database.

BACKGROUND: The use of ventricular assist device (VAD) in children has increased, but the decision of left VAD (LVAD) vs biventricular support remains a challenge. Children who undergo LVAD placement are at risk for right ventricular failure (RHF), but the incidence has not been described. METHODS: Analysis was performed for patients <18 years old who underwent durable LVAD placement within the Pedimacs registry (September 19, 2012-February 28, 2017), excluding single ventricle morphology and temporary devices. RHF was defined as the need for right ventriculalr assist device (RVAD) or prolonged inotrope use between 1 week to 1 month and 1 to 3 months. End-points included death, heart transplant (HT), and recovery. RESULTS: A total of 272 durable LVAD were placed of which 37 died on device over 24 month follow-up, primarily from multiorgan failure and neurologic dysfunction. RVAD occurred in 12 children at median 8.5 days, with 9 undergoing HT and 3 dying on device. In patients with only LVAD, RHF was present in 111/207 (55%) between 1 week to 1 month and 28/116 (25%) between 1 and 3 months. Younger age, smaller weight, Intermacs profile 1, chemical paralysis, and pulsatile flow VAD were associated with RHF. RHF was associated with increased risk of death on device at both >1 month (hazard ratio 3.2, 95% CI 1.4-7.7, p = 0.007) and >3 month (hazard ratio 6.9, 95% CI 2-23.1, p = 0.002). CONCLUSIONS: In children, RHF is common after durable LVAD implantation, but subsequent RVAD is relatively rare. RHF in children, as indicated by prolonged inotrope support, was associated with an increased risk of death on the device. Whether early RVAD support and higher waitlist status may improve the outcome remains unknown.

Use of bivalirudin as a primary anticoagulant in a child during Berlin Heart EXCOR ventricular assist device support.

We describe our experience of bivalirudin use, a newer direct thrombin inhibitor, in an infant who was supported with Berlin Heart EXCOR VAD (Berlin VAD) as bridge to transplant for 122 days without complications and without need for pump exchange. An 11-month-old girl with dilated cardiomyopathy with acute heart failure was awaiting cardiac transplant. Lack of improvement despite maximizing medical therapy and anticipating a prolonged waitlist time, she was supported with Berlin LVAD as a bridge to transplant. Anticoagulation with bivalirudin was started and titrated with a goal partial thromboplastin time of 60-90 seconds. Therapeutic anticoagulation was achieved with bivalirudin for 50% of the days (61/122 days) on a dose of 2.1 mg/kg/hour and in a narrow dose range of 1.9 to 2.3 mg/kg/hour for 80% of the days (98/122 days). Antiplatelet regimen was started initially with aspirin and clopidogrel added later. She was supported for 122 days on a single pump without any evidence of thrombus or need for pump change. Berlin VAD explant and orthotopic heart transplant with biatrial anastomosis were performed uneventfully. Explanted Berlin VAD had no evidence of clot/fibrin or thrombus formation. The child was discharged to home uneventfully 15 days after cardiac transplant.

Early outcomes for low-risk pediatric heart transplant recipients and steroid avoidance: A multicenter cohort study (Clinical Trials in Organ Transplantation in Children - CTOTC-04).

BACKGROUND: Immunosuppression strategies have changed over time in pediatric heart transplantation. Thus, comorbidity profiles may have evolved. Clinical Trials in Organ Transplantation in Children-04 is a multicenter, prospective, cohort study assessing the impact of pre-transplant sensitization on outcomes after pediatric heart transplantation. This sub-study reports 1-year outcomes among recipients without pre-transplant donor-specific antibodies (DSAs). METHODS: We recruited consecutive candidates (<21 years) at 8 centers. Sensitization status was determined by a core laboratory. Immunosuppression was standardized as follows: Thymoglobulin induction with tacrolimus and/or mycophenolate mofetil maintenance. Steroids were not used beyond 1 week. Rejection surveillance was by serial biopsy. RESULTS: There were 240 transplants. Subjects for this sub-study (n = 186) were non-sensitized (n = 108) or had no DSAs (n = 78). Median age was 6 years, 48.4% were male, and 38.2% had congenital heart disease. Patient survival was 94.5% (95% confidence interval, 90.1-97.0%). Freedom from any type of rejection was 67.5%. Risk factors for rejection were older age at transplant and presence of non-DSAs pre-transplant. Freedom from infection requiring hospitalization/intravenous anti-microbials was 75.4%. Freedom from rehospitalization was 40.3%. New-onset diabetes mellitus and post-transplant lymphoproliferative disorder (PTLD) occurred in 1.6% and 1.1% of subjects, respectively. There was no decline in renal function over the first year. Corticosteroids were used in 14.5% at 1 year. CONCLUSIONS: Pediatric heart transplantation recipients without DSAs at transplant and managed with a steroid avoidance regimen have excellent short-term survival and a low risk of first-year diabetes mellitus and PTLD. Rehospitalization remains common. These contemporary observations allow for improved caregiver and/or patient counseling and provide the necessary outcomes data to help design future randomized controlled trials.

Ventricular Arterial Coupling: A Novel Echocardiographic Risk Factor for Disease Progression in Pediatric Dilated Cardiomyopathy.

In adult heart failure (HF) patients, a higher ventricular arterial (VA) coupling ratio measured non-invasively is associated with worse HF prognosis and response to treatment. There are no data regarding the relationship of VA coupling to outcome in pediatric dilated cardiomyopathy (DCM) patients. We investigated the association of VA coupling ratio with worse outcome (mechanical circulatory support, transplant, or death) in 48 children with DCM and 97 age-gender matched controls. Mean age at presentation was 9 ± 7 years; DCM patients had a higher arterial elastance (3.8 ± 1.7 vs 2.7 ± 0.7 respectively p = 0.001), a lower LV elastance (1.1 ± 0.65 vs 4.5 ± 1.4, respectively p = 0.001) and higher VA coupling ratio (5.0 ± 3.9 vs 0.34 ± 0.14, respectively p = 0.001). Outcome events occurred in 27/48 (56%) patients. Patients with an outcome event had a higher NYHA class (p = 0.001), lower LV elastance (0.8 ± 0.47 vs 1.6 ± 0.57, respectively p = 0.001), higher arterial elastance (4.5 ± 1.8 vs 2.9 ± 1.1, respectively p = 0.002), and a higher VA coupling ratio (7.1 ± 3.8 vs 2.2 ± 1.5, respectively p = 0.001) compared to those without. In a multivariate CART analysis, VA coupling was the top and only discriminator of poor outcome. In conclusion, a higher VA coupling ratio is associated with worse outcome in pediatric patients with DCM. VA coupling is promising as a bedside analysis tool that may provide insight into the mechanisms of HF in pediatric DCM and identify potential targets for therapy.

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.

Outcomes of Early Adolescent Donor Hearts in Adult Transplant Recipients.

OBJECTIVES: This study sought to determine outcomes of adult recipients of early adolescent (EA) (10 to 14 years) donor hearts. BACKGROUND: Despite a shortage of donor organs, EA donor hearts (not used for pediatric patients) are seldom used for adults because of theoretical concerns for lack of hormonal activation and changes in left ventricular mass. Nonetheless, the outcomes of adult transplantation using EA donor hearts are not clearly established. METHODS: All adult (≥18 years of age) heart transplant recipients in the United Network for Organ Sharing database between April 1994 and September 2015 were eligible for this analysis. Recipients of EA donor hearts were compared with recipients of donor hearts from the usual adult age group (ages 18 to 55 years). Main outcomes were all-cause mortality and cardiac allograft vasculopathy up to 5 years, and primary graft failure up to 90 days post-transplant. Propensity score analysis was used to identify a cohort of recipients with similar baseline characteristics. RESULTS: Of the 35,054 eligible adult recipients, 1,123 received hearts from EA donors and 33,931 from usual-age adult donors. With the use of propensity score matching, 944 recipients of EA donor hearts were matched to 944 recipients of usual-age adult donor hearts. There was no difference in 30-day, 1-year, 3-year, and 5-year recipient survival or primary graft failure rates in the 2 groups using both Cox hazards ratio and Kaplan-Meier analysis. Of note, adult patients who received EA donor hearts had a trend toward less cardiac allograft vasculopathy (Cox hazard ratio, 0.80; 95% confidence interval: 0.62 to 1.01; p = 0.07). CONCLUSIONS: In this largest analysis to date, we found strong evidence that EA donor hearts, not used for pediatric patients, can be safely transplanted in appropriate adult patients and have good outcomes. This finding should help increase the use of EA donor hearts.

Plasmacytoma-like Posttransplant Lymphoproliferative Disorder in a Pediatric Heart Transplant Recipient.

Posttransplant lymphoproliferative disorder (PTLD) is a diversely manifesting group of lymphoid or plasmacytic proliferations found in solid organ and bone marrow transplant recipients. PTLD occurs as a result of immunosuppression and is often driven by the Epstein Barr virus. Although most commonly of B-cell origin, similar to B-cell lymphomas, PTLD can rarely present as a plasmacytic process, resembling multiple myeloma. Although more common in adults, 8 cases of plasmacytoma-like PTLD have been reported in pediatric renal and combined small bowel-liver transplant recipients. Here, we present a rare report of a plasmacytoma-like PTLD case in a pediatric heart transplant recipient.

Outcomes and risk factors for listing for heart transplantation after the Norwood procedure: An analysis of the Single Ventricle Reconstruction Trial.

BACKGROUND: Infants with hypoplastic left heart syndrome after palliation have the worst survival among heart transplant recipients. Heart transplantation is often reserved for use in patients with sub-optimal results after palliative surgery. This study characterized outcomes after listing in infants with a single ventricle who had undergone the Norwood procedure and identified predictors of the decision to list for heart transplantation. METHODS: The public-use database from the multicenter, prospective randomized Single Ventricle Reconstruction trial was used to identify patients who were listed for heart transplantation. Outcomes on the waiting list and after transplantation were determined. Risk factors were compared between those who were listed and those who survived without listing. RESULTS: Among 555 patients, 33 patients (5.9%) were listed and 18 underwent heart transplantation. Mortality was 39% while waiting for a heart and was 33% after heart transplantation. Overall, 1-year survival after listing (including death after transplantation) was 48%. Factors associated with listing were a lower right ventricular fractional area change at birth, non-hypoplastic left heart syndrome diagnosis, and a more complicated post-Norwood course, defined as a higher need for extracorporeal membrane oxygenation, longer intensive care unit stay, more complications, and a higher number of discharge medications. CONCLUSIONS: Worse right ventricular function, non-hypoplastic left heart syndrome diagnosis, and complex intensive care unit stay were significant risk factors for listing for heart transplantation after the Norwood procedure. Heart transplantation as a rescue procedure after the Norwood procedure in the first year of life carries a significant risk of mortality.

Cardiomyopathy Phenotypes and Outcomes for Children With Left Ventricular Myocardial Noncompaction: Results From the Pediatric Cardiomyopathy Registry.

BACKGROUND: Left ventricular noncompaction (LVNC) is a distinct form of cardiomyopathy characterized by hypertrabeculation of the left ventricle. The LVNC phenotype may occur in isolation or with other cardiomyopathy phenotypes. Prognosis is incompletely characterized in children. METHODS AND RESULTS: According to diagnoses from the National Heart, Lung, and Blood Institute-funded Pediatric Cardiomyopathy Registry from 1990 to 2008, 155 of 3,219 children (4.8%) had LVNC. Each LVNC patient was also classified as having an associated echocardiographically diagnosed cardiomyopathy phenotype: dilated (DCM), hypertrophic (HCM), restrictive (RCM), isolated, or indeterminate. The time to death or transplantation differed among the phenotypic groups (P = .035). Time to listing for cardiac transplantation significantly differed by phenotype (P < .001), as did time to transplantation (P = .015). The hazard ratio for death/transplantation (with isolated LVNC as the reference group) was 4.26 (95% confidence interval [CI] 0.78-23.3) for HCM, 6.35 (95% CI 1.52-26.6) for DCM, and 5.66 (95% CI 1.04-30.9) for the indeterminate phenotype. Most events occurred in the 1st year after diagnosis. CONCLUSIONS: LVNC is present in at least 5% of children with cardiomyopathy. The specific LVNC-associated cardiomyopathy phenotype predicts the risk of death or transplantation and should inform clinical management.