Sacubitril/Valsartan in Pediatric Heart Failure (PANORAMA-HF): A Randomized, Multicenter, Double-Blind Trial.

BACKGROUND: Sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor (ARNI), is an established treatment for heart failure (HF) with reduced left ventricular ejection fraction. It has not been rigorously compared with angiotensin-converting enzyme inhibitors in children. PANORAMA-HF (Prospective Trial to Assess the Angiotensin Receptor Blocker Neprilysin Inhibitor LCZ696 Versus Angiotensin-Converting Enzyme Inhibitor for the Medical Treatment of Pediatric HF) is a randomized, double-blind trial that evaluated the pharmacokinetics and pharmacodynamics (PK/PD), safety, and efficacy of sacubitril/valsartan versus enalapril in children 1 month to <18 years of age with HF attributable to systemic left ventricular systolic dysfunction (LVSD). METHODS: Children with HF attributable to LVSD were randomized to sacubitril/valsartan versus enalapril to assess the efficacy and safety of sacubitril/valsartan at 52 weeks of follow-up. The primary end point of the study was to determine whether sacubitril/valsartan was superior to enalapril for the treatment of pediatric patients with HF attributable to systemic LVSD, assessed using a primary global rank end point consisting of ranking patients from worst to best on the basis of clinical events such as death, listing for urgent heart transplant, mechanical life support requirement, worsening HF, New York Heart Association (NYHA)/Ross class, Patient Global Impression of Severity (PGIS), and Pediatric Quality of Life Inventory physical functioning domain. The change from baseline to 52 weeks in NT-proBNP (N-terminal pro-B-type natriuretic peptide) was an exploratory end point. RESULTS: A total of 375 children (mean age, 8.1±5.6 years; 52% female) were randomized to sacubitril/valsartan (n=187) or enalapril (n=188). At week 52, no significant difference was observed between the 2 treatment arms in the global rank end point (Mann-Whitney probability, 0.52 [95% CI, 0.47-0.58]; Mann-Whitney odds, 0.91 [95% CI, 0.72-1.14]; P=0.42). At week 52, clinically meaningful reductions were observed in both treatment arms in NYHA/Ross, PGIS, Patient Global Impression of Change, and NT-proBNP, without significant differences between groups. Adverse events were similar between treatment arms (incidence: sacubitril/valsartan, 88.8%; enalapril, 87.8%), and the safety profile of sacubitril/valsartan was acceptable in children. CONCLUSIONS: In this study, sacubitril/valsartan did not show superiority over enalapril in the treatment of children with HF attributable to systemic LVSD using the prespecified global rank end point. However, both treatment arms showed clinically meaningful improvements over 52 weeks. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02678312.

Impact of ventricular assist device use on pediatric heart transplant waitlist mortality: Analysis of the scientific registry of transplant recipients database.

BACKGROUND: Children awaiting heart transplant (Tx) have a high risk of death due to donor organ scarcity. Historically, ventricular assist devices (VADs) reduced waitlist mortality, prompting increased VAD use. We sought to determine whether the VAD survival benefit persists in the current era. METHODS: Using the Scientific Registry of Transplant Recipients, we identified patients listed for Tx between 3/22/2016 and 9/1/2020. We compared characteristics of VAD and non-VAD groups at Tx listing. Cox proportional hazards models were used to identify risk factors for 1-year waitlist mortality. RESULTS: Among 5054 patients, 764 (15%) had a VAD at Tx listing. The VAD group was older with more mechanical ventilation and renal impairment. Unadjusted waitlist mortality was similar between groups; the curves crossed ~90 days after listing (p = .55). In multivariable analysis, infant age (HR 2.77, 95%CI 2.13-3.60), Black race (HR 1.57, 95%CI 1.31-1.88), congenital heart disease (HR 1.23, 95%CI 1.04-1.46), renal impairment (HR 2.67, 95%CI 2.19-3.26), inotropes (HR 1.28, 95%CI 1.09-1.52), and mechanical ventilation (HR 2.23, 95%CI 1.84-2.70) were associated with 1-year waitlist mortality. VADs were not associated with mortality in the first 90 waitlist days but were protective for those waiting ≥90 days (HR 0.43, 95%CI 0.26-0.71). CONCLUSIONS: In the current era, VADs reduce waitlist mortality, but only for those waitlisted ≥90 days. The differential effect by race, size, and VAD type is less clear. These findings suggest that Tx listing without VAD may be reasonable if a short waitlist time is anticipated, but VADs may benefit those expected to wait >90 days.

Limited Relationship Between Echocardiographic Measures and Electrocardiographic Markers of Left Ventricular Size in Healthy Children.

Pediatric ECG standards have been defined without echocardiographic confirmation of normal anatomy. The Pediatric Heart Network Normal Echocardiogram Z-score Project provides a racially diverse group of healthy children with normal echocardiograms. We hypothesized that ECG and echocardiographic measures of left ventricular (LV) dimensions are sufficiently correlated in healthy children to imply a clinically meaningful relationship. This was a secondary analysis of a previously described cohort including 2170 digital ECGs. The relationship between 6 ECG measures associated with LV size were analyzed with LV Mass (LVMass-z) and left ventricular end-diastolic volume (LVEDV-z) along with 11 additional parameters. Pearson or Spearman correlations were calculated for the 78 ECG-echocardiographic pairs with regression analyses assessing the variance in ECG measures explained by variation in LV dimensions and demographic variables. ECG/echocardiographic measurement correlations were significant and concordant in 41/78 (53%), though many were significant and discordant (13/78). Of the 6 ECG parameters, 5 correlated in the clinically predicted direction for LV Mass-z and LVEDV-z. Even when statistically significant, correlations were weak (0.05-0.24). R2 was higher for demographic variables than for echocardiographic measures or body surface area in all pairs, but remained weak (R2 ≤ 0.17). In a large cohort of healthy children, there was a positive association between echocardiographic measures of LV size and ECG measures of LVH. These correlations were weak and dependent on factors other than echocardiographic or patient derived variables. Thus, our data support deemphasizing the use of solitary, traditional measurement-based ECG markers traditionally thought to be characteristic of LVH as standalone indications for further cardiac evaluation of LVH in children and adolescents.

Virtual cardiac fitness training in pediatric heart transplant patients: A pilot study.

BACKGROUND: Cardiac fitness training in pediatric heart transplant recipients can improve functional capacity. Widespread implementation has been limited mostly due to logistical constraints, specifically related to travel. The aim of this study was to implement and assess a virtual cardiac fitness program for pediatric heart transplant patients. METHODS: Participants were between the age of 10 and 20 years old. All subjects completed an initial 6MWT, strength/flexibility assessment, and QOL assessment with the PROMIS measurement. Participants then underwent a 16-week intervention with exercise sessions twice weekly for 30 min with a trained exercise physiologist over a virtual platform. At the end of the intervention period, participants repeated a 6MWT, strength/flexibility assessment, and PROMIS measurement. Throughout the study, patients wore a FitBit accelerometer to monitor daily activity levels. RESULTS: Thirteen individuals were enrolled. Mean age was 15.4 years (SD =3.4) with a mean post-transplant period of 9.7 years (SD = 4.3). Session attendance was 83%. Post-intervention measurements showed improvements in 6MWT (median, +21 m, p = .02), push-up repetitions (median, +5 rep, p = .0005), wall-sit duration (median, +10 s, p = .001), plank duration (median, +9 s, p = .03), sit-up repetitions (median, +7 rep, p = .002), and sit and reach distance (median, +5 cm, p = .04). PROMIS measurement showed significant improvements in self-reported fatigue (Δz-score, -7.7, p = .008) and sleep impairment (Δz-score, -5.9, p = .002). Average daily step count increased 1464 steps per day per patient (p = .008). CONCLUSION: We have demonstrated the successful implementation of a virtual cardiac fitness with excellent adherence and improvement in physical fitness and QOL metrics.

Incidence of cytomegalovirus DNAemia in pediatric kidney, liver, and heart transplant recipients: Efficacy and risk factors associated with failure of weight-based dosed valganciclovir prophylaxis.

BACKGROUND: Cytomegalovirus (CMV) is associated with morbidity and mortality in solid organ transplant recipients (SOTR). Valganciclovir (VGC) is extensively used for prophylaxis. Optimal dosing in children, risk factors for failure, and the impact of dose adjustments on CMV DNAemia is not well established. METHODS: This retrospective cohort study of pediatric SOTR transplanted between 2010-2018 evaluated the epidemiology of CMV DNAemia and used Cox-regression to assess the risk factors for CMV DNAemia within one-year following SOTR. RESULTS: In 393 pediatric SOTR (heart [96, 24.4%], kidney [180, 45.6%], liver [117, 29.8%]; median age 9.5 ± 0.3 years), overall CMV DNAemia incidence was 6.6/10 000 days (95%CI 5.1/10 000-7.9/10 000) and varied by organ groups: heart 8.2/10 000 days (95%CI 4.9/10 000-11.4/10 000), kidney 5.8/10 000 days (95%CI 3.9/10 000-7.8/10 000), liver 6.2/10 000 days (95%CI 3.7/10 000-8.7/10 000). CMV DNAemia was detected in 75 of 275 (27.2%) patients who received prophylaxis (40 cases occurred during prophylaxis and 35 occurred after completion of prophylaxis). The median VGC dose given according to institutional weight-based algorithm was approximately 1.5-fold lower than the manufacturer-recommended dose. This discordance was more prominent at younger age groups (3.2-fold lower in <2-year-old [100 mg versus 325 mg], 2.5-fold lower in <6-year-old [200 mg versus 447 mg]). Dose reduction due to adverse events was an independent risk factor for breakthrough CMV DNAemia (hazard ratio 2.2, 95%CI 1.2-3.8) among patients with similar age, CMV risk stratification, starting VGC dose, immunosuppressive therapy, and organ group. CONCLUSION: CMV events occurred while on VGC prophylaxis. Weight-based VGC may prevent supratherapeutic VGC exposure especially in younger children. Dose reduction of VGC prophylaxis for adverse event management places patients at an increased risk for CMV DNAemia suggesting other agents with fewer adverse effects should be considered and need to be studied in children.

Outcomes after initial heart failure consultation in Fontan patients.

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

Exercise Recommendations in Pediatric HCM: Variation and Influence of Provider Characteristics.

Pediatric Hypertrophic Cardiomyopathy (HCM) is associated with sudden cardiac death (SCD) that can be related to physical activity. Without pediatric specific guidelines, recommendations for activity restriction may be varied. Therefore, our aim is to determine the current practice and variability surrounding exercise clearance recommendations (ER) in pediatric HCM referral centers as well as provider and patient characteristics that influence them. We designed a survey that was distributed to the Pediatric Heart Transplant Study (PHTS) providers and members of the Pediatric and Adult Congenital Electrophysiology Society (PACES) querying provider demographics and patient variables from 2 patient vignettes. The study is a multicenter survey of current practice of specialized providers caring for pediatric HCM patients. Survey of PHTS and PACES providers via email to the respective listservs with a response rate of 28% and 91 overall completing the entire survey after self-identifying as providers for pediatric HCM patients at their center. ER varies for pediatric HCM and is associated with provider training background as well as personal and professional history. Of the 91 providers who completed the survey, 42% (N = 38) trained in pediatric electrophysiology (EP), and 40% (N = 36) in pediatric heart failure (HF). Responses varied and only 53% of providers cleared for mild to moderate activity for the patient in Vignette 1, which is more in line with recent published adult guidelines. ER in both vignettes was significantly associated with type of training background. EP providers were more likely to recommend no restriction (27.8% vs 5.9%) than HF providers even when controlling for provider age and time out of training. Syncope with exercise was deemed "Most Important" by 81% of providers when making ER. ER for pediatric HCM are variable and the majority of providers make ER outside of previously published adult guidelines. Furthermore, ER are influenced by provider background and experience. Further study is needed for risks and benefits of physical activity in this population to inform the development of pediatric specific guidelines.

Pretransplantation and Post-Transplantation Liver Disease Assessment in Adolescents Undergoing Isolated Heart Transplantation for Fontan Failure.

OBJECTIVE: To describe the assessment of Fontan-associated liver disease and determine the clinical and imaging measures that may identify hepatic morbidity risk in isolated heart transplantation candidates and trend those measures post-isolated heart transplantation. STUDY DESIGN: Retrospective analysis of pre-isolated heart transplantation and post-isolated heart transplantation Fontan-associated liver disease (FALD) status using blood tests, magnetic resonance imaging (MRI), and liver biopsy analysis within 6 months before isolated heart transplantation and 12 months after isolated heart transplantation in 9 consecutive patients with Fontan. Pre- and post-isolated heart transplantation standard laboratory values; varices, ascites, splenomegaly, thrombocytopenia (VAST) score; Fontan liver MRI score; liver biopsy scores; Model for End-stage Liver Disease (MELD); MELD excluding the International Normalized Ratio (MELD-XI); AST to platelet ratio index, and cardiac catheterization data were compared. RESULTS: Pretransplantation maximum MELD and MELD-XI was 15 and 16, respectively. Central venous pressures and VAST scores decreased significantly post-transplantation. In 5 paired studies, Fontan liver MRI score maximum was 10 pretransplantation and decreased significantly post-transplantation. Arterially enhancing nodules on MRI persisted in 2 patients post-transplantation. Pretransplantation and post-transplantation liver biopsy scores did not differ in 4 paired biopsy specimens. CONCLUSIONS: Patients with FALD and MELD <15, MELD-XI <16, Fontan liver MRI score <10, and VAST score ≤2 can have successful short-term isolated heart transplantation outcomes. Liver MRI and VAST scores improved post-transplantation. Post-transplantation liver biopsy scores did not change significantly. Pretransplantation liver biopsy demonstrating fibrosis alone should not exclude consideration of isolated heart transplantation. The persistence of hepatic vascular remodeling and fibrosis post-isolated heart transplantation suggests that continued surveillance for hepatic complications post-transplantation for patients with Fontan is reasonable.

Cryptosporidiosis among solid organ transplant recipient attendees at a summer camp.

We report a cluster of pediatric cryptosporidiosis infections among solid organ transplant recipients at a summer camp in Georgia, USA. A retrospective cohort study was conducted to investigate the risk factors for infection. A total of 118 campers attended the camp during July 23-28, 2017. The overall attack rate among campers during the outbreak was 11% (13/118). Sanger-based amplicon sequencing of stool specimens from 7 (80%) campers identified Cryptosporidium hominis as the suspected etiologic agent. All infected campers were heart or kidney transplant recipients receiving immunosuppressive therapy. The median reported symptom duration was 12 days (range 6-18 days) and 9 (69.2%) were hospitalized for at least one night (median length of stay 5 days, range 2-16 days). There were no deaths or acute rejection events attributed to infection. The results of the epidemiologic and environmental investigation suggest a recreational pool as the presumed source, although there was no direct evidence to support this. Many long-term interventions were implemented, and there have been no further outbreaks at the camp in the following two years. This outbreak demonstrates that cryptosporidiosis may be associated with notable burden in pediatric transplant recipients, and illustrates the challenges associated with source identification and containment.

A preliminary investigation of sleep quality and patient-reported outcomes in pediatric solid organ transplant candidates.

The current cross-sectional, single-center study aimed to examine sleep quality in a sample of adolescents awaiting solid organ transplantation and to explore associations between sleep quality and both health-related quality of life and barriers to adherence. Thirty adolescents between the ages of 12 and 18 years (M age = 15.26, SD = 1.89) who were awaiting transplantation participated in this study. Participants completed measures of sleep quality, health-related quality of life, and barriers to adherence. T test and correlational analyses were performed to examine study aims. Adolescents awaiting transplantation had significantly lower levels of overall sleep quality compared to published norms of healthy peers. Domains of sleep quality were positively related to emotional and psychosocial health-related quality of life. Sleep quality domains were also negatively related to adherence barriers. This study provides preliminary evidence demonstrating that sleep quality among transplant candidates is compromised, and that poor sleep quality is related to adolescents' functioning across a number of domains during the pretransplant period. Results highlight the clinical importance of assessing and targeting sleep functioning in adolescents awaiting transplantation in order to reduce the negative influence of suboptimal sleep on functioning during this vulnerable period.

Biventricular support with HeartWare ventricular assist device in a pediatric patient.

Use of ventricular assist devices is increasing in the pediatric population. This has included the extended use of adult continuous-flow devices in the pediatric population. In a minority of cases, biventricular support may be needed. In these situations, biventricular support with continuous-flow devices can be surgically challenging, and therefore, only few cases have been reported. Here, we present a case of implantation of two HeartWare HVAD devices for biventricular support for a decompensating patient with acute myocarditis as well as present an alternative implantation surgical strategy.

Multimethod Assessment of Medication Nonadherence and Barriers in Adolescents and Young Adults With Solid Organ Transplants.

Objective: To (a) examine levels of medication nonadherence in adolescent and young adult (AYA) solid organ transplant recipients based on AYA- and caregiver proxy-reported nonadherence to different medication types and the medication-level variability index (MLVI) for tacrolimus, and (b) examine associations of adherence barriers and AYA and caregiver emotional distress symptoms with reported nonadherence and the MLVI. Method: The sample included 47 AYAs (M age = 16.67 years, SD = 1.74; transplant types: 25% kidney, 47% liver, 28% heart) and their caregivers (94 total participants). AYAs and caregivers reported on AYAs' adherence barriers and their own emotional functioning. Nonadherence was measured with AYA self- and caregiver proxy-report and the MLVI for tacrolimus. Results: The majority of AYAs and caregivers denied nonadherence, with lower rates of nonadherence reported for antirejection medications. In contrast, 40% of AYAs' MLVI values indicated nonadherence to tacrolimus. AYAs and caregivers who verbally acknowledged nonadherence had more AYA barriers and greater caregiver emotional distress symptoms compared with those who denied nonadherence. AYAs with MLVIs indicating nonadherence had more barriers than AYAs with MLVIs indicating adherence. Conclusions: Multimethod nonadherence evaluations for AYA transplant recipients should assess objective nonadherence using the MLVI, particularly in light of low reported nonadherence rates for antirejection medications. Assessments should include adherence barriers measures, given associations with the MLVI, and potentially prioritize assessing barriers over gauging nonadherence via self- or proxy-reports. Caregiver emotional distress symptoms may also be considered to provide insight into family or environmental barriers to adherence.

A prospective multicenter feasibility study of a miniaturized implantable continuous flow ventricular assist device in smaller children with heart failure.

BACKGROUND: There is no FDA-approved left ventricular assist device (LVAD) for smaller children permitting routine hospital discharge. Smaller children supported with LVADs typically remain hospitalized for months awaiting heart transplant-a major burden for families and a challenge for hospitals. We describe the initial outcomes of the Jarvik 2015, a miniaturized implantable continuous flow LVAD, in the NHLBI-funded Pumps for Kids, Infants, and Neonates (PumpKIN) study, for bridge-to-heart transplant. METHODS: Children weighing 8 to 30 kg with severe systolic heart failure and failing optimal medical therapy were recruited at 7 centers in the United States. Patients with severe right heart failure and single-ventricle congenital heart disease were excluded. The primary feasibility endpoint was survival to 30 days without severe stroke or non-operational device failure. RESULTS: Of 7 children implanted, the median age was 2.2 (range 0.7, 7.1) years, median weight 10 (8.2 to 20.7) kilograms; 86% had dilated cardiomyopathy; 29% were INTERMACS profile 1. The median duration of Jarvik 2015 support was 149 (range 5 to 188) days where all 7 children survived including 5 to heart transplant, 1 to recovery, and 1 to conversion to a paracorporeal device. One patient experienced an ischemic stroke on day 53 of device support in the setting of myocardial recovery. One patient required ECMO support for intractable ventricular arrhythmias and was eventually transplanted from paracorporeal biventricular VAD support. The median pump speed was 1600 RPM with power ranging from 1-4 Watts. The median plasma free hemoglobin was 19, 30, 19 and 30 mg/dL at 7, 30, 90 and 180 days or time of explant, respectively. All patients reached the primary feasibility endpoint. Patient-reported outcomes with the device were favorable with respect to participation in a full range of activities. Due to financial issues with the manufacturer, the study was suspended after consent of the eighth patient. CONCLUSION: The Jarvik 2015 LVAD appears to hold important promise as an implantable continuous flow device for smaller children that may support hospital discharge. The FDA has approved the device to proceed to a 22-subject pivotal trial. Whether this device will survive to commercialization remains unclear because of the financial challenges faced by industry seeking to develop pediatric medical devices. (Supported by NIH/NHLBI HHS Contract N268201200001I, clinicaltrials.gov 02954497).

Mislocalization of pathogenic RBM20 variants in dilated cardiomyopathy is caused by loss-of-interaction with Transportin-3.

Severe forms of dilated cardiomyopathy (DCM) are associated with point mutations in the alternative splicing regulator RBM20 that are frequently located in the arginine/serine-rich domain (RS-domain). Such mutations can cause defective splicing and cytoplasmic mislocalization, which leads to the formation of detrimental cytoplasmic granules. Successful development of personalized therapies requires identifying the direct mechanisms of pathogenic RBM20 variants. Here, we decipher the molecular mechanism of RBM20 mislocalization and its specific role in DCM pathogenesis. We demonstrate that mislocalized RBM20 RS-domain variants retain their splice regulatory activity, which reveals that aberrant cellular localization is the main driver of their pathological phenotype. A genome-wide CRISPR knockout screen combined with image-enabled cell sorting identified Transportin-3 (TNPO3) as the main nuclear importer of RBM20. We show that the direct RBM20-TNPO3 interaction involves the RS-domain, and is disrupted by pathogenic variants. Relocalization of pathogenic RBM20 variants to the nucleus restores alternative splicing and dissolves cytoplasmic granules in cell culture and animal models. These findings provide proof-of-principle for developing therapeutic strategies to restore RBM20's nuclear localization in RBM20-DCM patients.

Breastfeeding practices in military families: a 12-month prospective population-based study in the national capital region.

Breastfeeding practices in military families have not been widely investigated. The objective of this study was to measure the prevalence and duration of breastfeeding among uniformed families and identify factors associated with breastfeeding. We conducted a prospective study of 253 mothers of new infants from July to December 2004. Initial information gathered included demographic data, feeding choices, and intended duration of breastfeeding. Follow-up surveys were conducted until 12 months postpartum. 51% of mothers were breastfeeding at 6 months and 25% at 1 year. Mothers on active duty were equally likely to breastfeed than non-active duty mothers. Officer mothers were 3 times more likely to breastfeed compared to enlisted mothers (p = 0.005). Mothers with higher education were twice as likely to breastfeed longer (p = 0.015). Families participating in Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) were 2.5 times less likely to breastfed at 1 year (p < 0.001). Our study shows a higher percentage of women initiating and maintaining breastfeeding compared to national data, but still less than current American Academy of Pediatrics guidelines. Our study suggests that to improve breastfeeding rates among uniformed families, more attention may need to be directed to younger, enlisted mothers and those families in a lower socioeconomic status or receiving WIC assistance.

Impaired ventilation during 6-min walk test in congenital central hypoventilation syndrome.

BACKGROUND: Patients with congenital central hypoventilation syndrome (CCHS) can develop hypoxemia and hypercapnia during exercise. However, there is limited literature on cardiorespiratory responses during submaximal exercise and their correlation with paired-like homeobox 2B (PHOX2B) genotype. OBJECTIVES: To assess oxygen saturation (SpO2 ), end-tidal carbon dioxide (ETCO2 ), heart rate (HR), and 6-min walk distance (6MWD) during a 6-min walk test (6MWT) in CCHS subjects and to correlate them with PHOX2B genotypes and assisted ventilation (AV) via tracheostomy. METHODS: In this cross-sectional study, subjects with CCHS performed 6MWT with continuous pulse oximetry, HR, and capnography recorded before and during the 6MWT. Medical records were reviewed for PHOX2B genotype and phenotype data. Patients were categorized based on PHOX2B genotype and AV via tracheostomy. RESULTS: Fifteen subjects aged 10.5 (interquartile range 7.9-16.2) years completed the 6MWT. Nine subjects used AV via tracheostomy. Seven (47%) subjects developed hypoxemia (SpO2 ≤ 90%, n = 7) and hypoventilation (ETCO2 ≥ 50 mmHg, n = 3) during the 6MWT. There was a significant decline from baseline SpO2 , increase from baseline ETCO2 , and increase in HR during the 6MWT (all p < 0.05). Subjects had decreased median percent predicted 6MWD (59.7% [50.6%-62.5%]). Nadir SpO2 (p = 0.029) and peak ETCO2 (p = 0.046) differed significantly between PHOX2B genotype groups but 6MWD did not (p = 0.8). CONCLUSION: Despite normal oxygenation and ventilation at rest and during sleep on AV, patients with CCHS can develop hypoxemia and hypercapnia during submaximal exercise. Our study highlights the importance of assessing ventilatory responses during submaximal exercise in patients with CCHS regardless of their PHOX2B genotype.

Congenital Central Hypoventilation Syndrome: Optimizing Care with a Multidisciplinary Approach.

Congenital central hypoventilation syndrome (CCHS) is a rare genetic disorder affecting respiratory control and autonomic nervous system function caused by variants in the paired-like homeobox 2B (PHOX2B) gene. Although most patients are diagnosed in the newborn period, an increasing number of patients are presenting later in childhood, adolescence, and adulthood. Despite hypoxemia and hypercapnia, patients do not manifest clinical features of respiratory distress during sleep and wakefulness. CCHS is a lifelong disorder. Patients require assisted ventilation throughout their life delivered by positive pressure ventilation via tracheostomy, noninvasive positive pressure ventilation, and/or diaphragm pacing. At different ages, patients may prefer to change their modality of assisted ventilation. This requires an individualized and coordinated multidisciplinary approach. Additional clinical features of CCHS that may present at different ages and require periodic evaluations or interventions include Hirschsprung's disease, gastrointestinal dysmotility, neural crest tumors, cardiac arrhythmias, and neurodevelopmental delays. Despite an established PHOX2B genotype and phenotype correlation, patients have variable and heterogeneous clinical manifestations requiring the formulation of an individualized plan of care based on collaboration between the pulmonologist, otolaryngologist, cardiologist, anesthesiologist, gastroenterologist, sleep medicine physician, geneticist, surgeon, oncologist, and respiratory therapist. A comprehensive multidisciplinary approach may optimize care and improve patient outcomes. With advances in CCHS management strategies, there is prolongation of survival necessitating high-quality multidisciplinary care for adults with CCHS.

Relationship of ventricular assist device support duration with pediatric heart transplant outcomes.

BACKGROUND: There is wide variability in the timing of heart transplant (HTx) after pediatric VAD implant. While some centers wait months before listing for HTx, others accept donor heart offers within days of VAD surgery. We sought to determine if HTx within 30 days versus ≥ 30 after VAD impacts post-HTx outcomes. METHODS: Children on VAD pre-HTx were extracted from the Pediatric Heart Transplant Study database. The primary endpoints were post-HTx length of hospital stay (LOS) and one-year survival. Confounding was addressed by propensity score weighting using inverse probability of treatment. Propensity scores were calculated based on age, blood type, primary cardiac diagnosis, decade, VAD type, and allosensitization status. RESULTS: A total of 1064 children underwent VAD prior to HTx between 2000 to 2018. Most underwent HTx ≥ 30 days post-VAD (70%). Infants made up 22% of both groups. Patients ≥ 12 years old were 42% of the < 30 days group and children 1 to 11 years comprised 47% of the ≥ 30 days group (p < 0.001). There was no difference in the prevalence of congenital heart disease vs. cardiomyopathy (p = 0.8) or high allosensitization status (p = 0.9) between groups. Post-HTx LOS was similar between groups (p = 0.11). One-year survival was lower in the < 30 days group (adjusted mortality HR 1.76, 95% CI 1.11-2.78, p = 0.016). CONCLUSIONS: A longer duration of VAD support prior to HTx is associated with a one-year survival benefit in children, although questions of patient complexity, post-VAD complications and the impact on causality remain. Additional studies using linked databases to understand these factors will be needed to fully assess the optimal timing for post-VAD HTx.

Left ventricular noncompaction: a rare cause of hydrops fetalis.

We present a case of isolated left ventricular noncompaction (LVNC), a severe congenital cardiomyopathy, which presented in the neonatal period as fetal hydrops. To our knowledge, this is the first child with LVNC presenting with hydrops fetalis to survive infancy. Once considered a uniformly fatal and extremely rare form of cardiomyopathy, LVNC has recently been shown to be more common than previously reported, with a varying range of clinical severity. Although long-term morbidity and mortality are not clearly known, recent work suggests better survivability than once reported.