The genetic architecture of pediatric cardiomyopathy.

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.

Left Ventricular Systolic Dysfunction in Patients Diagnosed With Hypertrophic Cardiomyopathy During Childhood: Insights From the SHaRe Registry.

BACKGROUND: The development of left ventricular systolic dysfunction (LVSD) in hypertrophic cardiomyopathy (HCM) is rare but serious and associated with poor outcomes in adults. Little is known about the prevalence, predictors, and prognosis of LVSD in patients diagnosed with HCM as children. METHODS: Data from patients with HCM in the international, multicenter SHaRe (Sarcomeric Human Cardiomyopathy Registry) were analyzed. LVSD was defined as left ventricular ejection fraction <50% on echocardiographic reports. Prognosis was assessed by a composite of death, cardiac transplantation, and left ventricular assist device implantation. Predictors of developing incident LVSD and subsequent prognosis with LVSD were assessed using Cox proportional hazards models. RESULTS: We studied 1010 patients diagnosed with HCM during childhood (<18 years of age) and compared them with 6741 patients with HCM diagnosed as adults. In the pediatric HCM cohort, median age at HCM diagnosis was 12.7 years (interquartile range, 8.0-15.3), and 393 (36%) patients were female. At initial SHaRe site evaluation, 56 (5.5%) patients with childhood-diagnosed HCM had prevalent LVSD, and 92 (9.1%) developed incident LVSD during a median follow-up of 5.5 years. Overall LVSD prevalence was 14.7% compared with 8.7% in patients with adult-diagnosed HCM. Median age at incident LVSD was 32.6 years (interquartile range, 21.3-41.6) for the pediatric cohort and 57.2 years (interquartile range, 47.3-66.5) for the adult cohort. Predictors of developing incident LVSD in childhood-diagnosed HCM included age <12 years at HCM diagnosis (hazard ratio [HR], 1.72 [CI, 1.13-2.62), male sex (HR, 3.1 [CI, 1.88-5.2), carrying a pathogenic sarcomere variant (HR, 2.19 [CI, 1.08-4.4]), previous septal reduction therapy (HR, 2.34 [CI, 1.42-3.9]), and lower initial left ventricular ejection fraction (HR, 1.53 [CI, 1.38-1.69] per 5% decrease). Forty percent of patients with LVSD and HCM diagnosed during childhood met the composite outcome, with higher rates in female participants (HR, 2.60 [CI, 1.41-4.78]) and patients with a left ventricular ejection fraction <35% (HR, 3.76 [2.16-6.52]). CONCLUSIONS: Patients with childhood-diagnosed HCM have a significantly higher lifetime risk of developing LVSD, and LVSD emerges earlier than for patients with adult-diagnosed HCM. Regardless of age at diagnosis with HCM or LVSD, the prognosis with LVSD is poor, warranting careful surveillance for LVSD, especially as children with HCM transition to adult care.

Research Gaps in Pediatric Heart Failure: Defining the Gaps and Then Closing Them Over the Next Decade.

Given the numerous opportunities and the wide knowledge gaps in pediatric heart failure, an international group of pediatric heart failure experts with diverse backgrounds were invited and tasked with identifying research gaps in each pediatric heart failure domain that scientists and funding agencies need to focus on over the next decade.

NT-proBNP for Predicting All-Cause Death and Heart Transplant in Children and Adults with Heart Failure.

Plasma N-terminal prohormone B-type natriuretic peptide (NT-proBNP) concentration is a heart failure (HF) biomarker in adults and children. Its prognostic value for HF-related events has been established only in adults. Therefore, we aimed to test the hypothesis that plasma NT-proBNP concentrations predicted the risk of heart transplantation or death in children with HF. We studied the medical records of 109 children with HF enrolled in the IBM Watson Explorys database and from 150 children enrolled in the Pediatric Cardiomyopathy Registry (PCMR). Nonlinear regression was used to assess the relationship between plasma NT-proBNP concentrations and the risk of events in the two cohorts. All children in the PCMR cohort had dilated cardiomyopathy. The Explorys cohort also included children with congenital cardiovascular malformations. Median plasma NT-proBNP concentrations were 1250 pg/mL and 184 pg/mL in the Explorys and PCMR cohorts, respectively. The percentage of deaths/heart transplantations was 7%/22%, over 2 years in the Explorys cohort and 3%/16% over 5 years in the PCMR cohort. Mean estimates of plasma NT-proBNP concentration indicative of half-maximum relative risk for events (EC50 values) at 2 and 5 years were 3730 pg/mL and 4199 pg/mL, respectively, values both close to the mean of 3880 pg/mL established for adults with HF. The plasma NT-proBNP concentration is suitable for estimating relative risk of mortality and heart transplantation in children with HF, independent of etiology and shows similar relations to clinical outcomes as in adults, indicating its likely value as a surrogate marker both for adult and pediatric HF.ClinicalTrials.gov Identifiers: NCT00005391 (May 26, 2000), NCT01873976 (June 10, 2013).

Hypertension: An Important But Reversible Cause of Systolic Dysfunction in a Cohort of Pediatric Patients.

Cardiac dysfunction due to hypertension (CDHTN) in pediatrics is not well described. We aimed to describe the presentation and outcomes of pediatric CDHTN and identify clinical features associated with resolution of dysfunction. A single-center retrospective cohort study of patients ≤ 21 years with CDHTN from January 2005-September 2020 was performed. Patients with systolic dysfunction without another cause, blood pressure > 95th percentile, and physician judgment that dysfunction was secondary to hypertension were included. Demographics, clinical characteristics, echocardiographic findings, and outcomes were examined using Fisher's exact and Mann-Whitney U tests. Multiple correspondence analysis was used to explore the relationship of resolution of dysfunction to clinical features. Thirty-four patients were analyzed at a median age of 10.9 (IQR 0.3-16.9) years. Patients were divided into groups < 1 year (n = 12) and ≥ 1 year (n = 22). Causes of hypertension were varied by age, with renovascular disease most common in infants (42%) and medical renal disease most common in older patients (77%). Echocardiography demonstrated mild LV dilation (median LV end-diastolic z-score 2.6) and mild LV hypertrophy (median LV mass z-score 2.4). Most patients (81%) had resolution of dysfunction, particularly infants (92%). One patient died and one patient was listed for heart transplant. None required mechanical circulatory support (MCS). No clinical features were statistically associated with resolution of dysfunction. Hypertension is an important but reversible cause of systolic dysfunction in children. Patients are likely to recover with low mortality and low utilization of MCS or transplantation. Further studies are needed to confirm features associated with resolution of dysfunction.

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.

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

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

Cardiac imaging and biomarkers for assessing myocardial fibrosis in children with hypertrophic cardiomyopathy.

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.

Reduced incidence of cardiac rejection in multi-organ transplants: A propensity matched study.

BACKGROUND: Rejection remains a primary cause of graft loss after heart transplant (HT). Recognizing the immunomodulation of multi-organ transplant can enhance our understanding of the mechanisms of cardiac rejection. METHODS: This retrospective cohort study identified patients from the UNOS database with isolated heart (H, N = 37 433), heart-kidney (HKi, N = 1516), heart-liver (HLi, N = 286), and heart-lung (HLu, N = 408) transplants from 2004 to 2019. Propensity score matching reduced baseline differences between groups. Outcomes included risk of rejection prior to transplant hospital discharge and within 1 year, and mortality within 1 year of transplant. RESULTS: In the propensity score matched data, the relative risk of being treated for rejection prior to transplant hospital discharge was 61% lower for HKi (RR .39, 95% CI .29, .53) and 87% lower for HLi (RR .13, 95% CI .05, .37) compared to H. Similarly, the probability of being treated for rejection in the first year after transplant remained lower in HKi (RR .45, 95% CI .35, .57) and HLi (RR .13, 95% CI .06, .28) compared to H. The 1-year survival analysis revealed an equivalent risk of death in HKi (HR .84, 95% CI .68, 1.03) and HLi (HR 1.41, 95% CI .83, 2.41) compared to H, while HLu had a higher risk of death in the first year after transplant (HR 1.65, 95% CI 1.17, 2.33). CONCLUSIONS: Recipients of HKi and HLi experience a reduced risk of rejection when compared to H, but an equivalent risk of 1 yr mortality. These findings have important implications for the future of HT medicine.

Temporal trends in primary payers in pediatric heart transplant and association with long-term survival.

BACKGROUND: Pediatric heart transplantation (HT) is resource intensive. In adults, there has been an increase in the proportion of HTs funded by public insurance, with post-HT outcomes inferior to those funded by private sources. Trends in the funding of pediatric HT and outcomes in children have not been described. METHODS: We queried the United Network for Organ Sharing (UNOS) database for children (<18 years) listed for and undergoing HT between 2004 and 2021. We identified the primary payer at listing, HT, 1 year, and 1-5 years following HT. Trends were analyzed using generalized logit models. Multivariable-extended Cox regression models were used to test the relationship between insurance type at the time of transplant and time to death or re-transplant. RESULTS: There were 6382 pediatric patients who underwent transplants and had either public or private insurance at the time of transplant. The percentage of patients with public insurance at the time of HT increased over time. Public insurance at the time of HT was associated with an increased risk of death or re-transplant beyond 2 months after HT (adjusted HR at 6 months = 1.43, 95% CI: 1.13-1.81, p = .003; adjusted HR at 9 months = 1.67, 95% CI: 1.17-2.37, p = .004). CONCLUSION: There has been a statistically significant trend toward increasing public insurance for children awaiting, at the time of, and after HT. Black patients and those with public insurance at HT have worse long-term outcomes. This study highlights ongoing disparities in pediatric HT and the need to focus efforts on achieving equitable outcomes.

Applying Practice Analysis to Develop a New Test Content Outline for the Pediatric Cardiology Certification Examination.

The evolving breadth and complexity of the contemporary pediatric cardiology specialty requires regular, systematic analysis of the practice to ensure that training and certification requirements address the demands of real-world clinical experience. We report the process of the American Board of Pediatrics (ABP) for conducting such a practice analysis and revising the test content outline (TCO) for the pediatric cardiology subspecialty certification exam. A panel of 15 pediatric cardiologists conducted seven 2-h virtual meetings, during which they identified 37 unique tasks that represent the work a pediatric cardiologist may reasonably expect to perform within the first 5 years after training. These tasks were grouped into nine performance domains, similar to the entrustable professional activities (EPA), previously endorsed by the ABP in collaboration with the pediatric cardiology education community, and which represent the critical activities of the profession. The panel then enumerated the knowledge, skills, and abilities necessary to perform each task. These deliberations resulted in two work products: a practice analysis document (PAD) and subspecialty board TCO based on testable knowledge, skills, and abilities. Survey assessments of the panel's work were then distributed to pediatric cardiology fellowship program directors and to practicing pediatric cardiologists for their input, which largely aligned with the panel's recommendations. Survey responses were considered in the final revisions of the PAD and TCO. This approach to practice analysis proved to be an efficient process for describing the work performed by today's pediatric cardiologists and the knowledge, skills, and abilities needed to competently perform that work.

Variation in hospital costs and resource utilisation after congenital heart surgery.

BACKGROUND: Children undergoing cardiac surgery have overall improving survival, though they consume substantial resources. Nationwide inpatient cost estimates and costs at longitudinal follow-up are lacking. METHODS: Retrospective cohort study of children <19 years of age admitted to Pediatric Health Information System administrative database with an International Classification of Diseases diagnosis code undergoing cardiac surgery. Patients were grouped into neonates (≤30 days of age), infants (31-365 days of age), and children (>1 year) at index procedure. Primary and secondary outcomes included hospital stay and hospital costs at index surgical admission and 1- and 5-year follow-up. RESULTS: Of the 99,670 cohort patients, neonates comprised 27% and had the highest total hospital costs, though daily hospital costs were lower. Mortality declined (5.6% in 2004 versus 2.5% in 2015, p < 0.0001) while inpatient costs rose (5% increase/year, p < 0.0001). Neonates had greater index diagnosis complexity, greater inpatient costs, required the greatest ICU resources, pharmacotherapy, and respiratory therapy. We found no relationship between hospital surgical volume, mortality, and hospital costs. Neonates had higher cumulative hospital costs at 1- and 5-year follow-up compared to infants and children. CONCLUSIONS: Inpatient hospital costs rose during the study period, driven primarily by longer stay. Neonates had greater complexity index diagnosis, required greater hospital resources, and have higher hospital costs at 1 and 5 years compared to older children. Surgical volume and in-hospital mortality were not associated with costs. Further analyses comprising merged clinical and administrative data are necessary to identify longer stay and cost drivers after paediatric cardiac surgery.

Sex Differences in Left Ventricular Assist Device-related Emergency Department Encounters in the United States.

BACKGROUND: There is a paucity of data regarding sex differences in the profiles and outcomes of ambulatory patients on left ventricular assist device (LVAD) support who present to the emergency department (ED). METHODS AND RESULTS: We performed a retrospective analysis of 57,200 LVAD-related ED patient encounters from the 2010 to 2018 Nationwide Emergency Department Sample. International Classification of Diseases Clinical Modification, Ninth Revision and Tenth Revision, codes identified patients aged 18 years or older with LVADs and associated primary and comorbidity diagnoses. Clinical characteristics and outcomes were stratified by sex and compared. Multivariable logistic regression was used to evaluate predictors of hospital admission and death. Female patient encounters comprised 27.2% of ED visits and occurred at younger ages and more frequently with obesity and depression (all P < .01). There were no sex differences in presentation for device complication, stroke, infection, or heart failure (all P > .05); however, female patient encounters were more often respiratory- and genitourinary or gynecological related (both P < .01). After adjustment for age group, diabetes, depression, and hypertension, male patient encounters had a 38% increased odds of hospital admission (95% confidence interval 1.20-1.58), but there was no sex difference in the adjusted odds of death (odds ratio 1.11, 95% confidence interval 0.86-1.45). CONCLUSIONS: Patient encounters of females on LVAD support have significantly different comorbidities and outcomes compared with males. Further inquiry into these sex differences is imperative to improve long-term outcomes.

Safety and Feasibility of Exercise Rehabilitation in Children with Ventricular Assist Devices.

Children with advanced heart failure may require ventricular assist devices (VAD) while awaiting heart transplantation. Currently, no data exist regarding the safety of exercise rehabilitation (ER) in children on VAD support. The purpose of this study was to determine the safety and feasibility of ER in children on VAD support awaiting heart transplantation. Eligible patients underwent VAD placement between 1998 and 2019; both inpatient and outpatient participants were included. After VAD implantation and when ambulatory, patients were enrolled in ER. Exercise sessions were scheduled three times a week and consisted of aerobic and musculoskeletal conditioning. A total of 29 patients (59% male, mean age 14 ± 3.2 years) were included with a median VAD duration of 120 ± 109 days. Cardiac diagnoses included cardiomyopathy (81%) and congenital heart disease (19%). VAD type included pulsatile (59%) and continuous-flow devices (41%). Eight hundred and sixty-four (85%) ER sessions were successfully completed and began at a mean of 49 days (range 19-108) after VAD implant. No adverse events, including episodes of hypotension, significant complex arrhythmia, or VAD malfunction occurred during exercise testing or ER, and no sessions were discontinued prematurely. Pediatric patients on VAD support can safely participate in ER with relatively high compliance, and sessions can be implemented early after VAD implantation. Given the safety profile, ER in pediatric VAD recipients, which is a modifiable pre-transplant risk factor that may improve functional capacity, warrants further study as a potential modality to improve post-transplant outcomes.

Center Variation in Indication and Short-Term Outcomes after Pediatric Heart Transplantation: Analysis of a Merged United Network for Organ Sharing - Pediatric Health Information System Cohort.

The relationship between center-specific variation in indication for pediatric heart transplantation and short-term outcomes after heart transplantation is not well described. We used merged patient- and hospital-level data from the United Network for Organ Sharing and the Pediatric Health Information Systems to analyze outcomes according to transplant indication for a cohort of children (≤ 21 years old) who underwent heart transplantation between 2004 and 2015. Outcomes included 30-day mortality, transplant hospital admission mortality, and hospital length of stay, with multivariable adjustment performed according to patient and center characteristics. The merged cohort reflected 2169 heart transplants at 20 U.S. centers. The median number of transplants annually at each center was 11.6, but ranged from 3.5 to 22.6 transplants/year. Congenital heart disease was the indication in the plurality of cases (49.2%), with cardiomyopathy (46%) and myocarditis (4.8%) accounting for the remainder. There was significant center-to-center variability in congenital heart disease as the principal indication, ranging from 15% to 66% (P < 0.0001). After adjustment, neither center volume nor proportion of indications for transplantation were associated with 30-day or transplant hospital admission mortality. In this large, merged pediatric cohort, variation was observed at center level in annual transplant volume and prevalence of indications for heart transplantation. Despite this variability, center volume and proportion of indications represented at a given center did not appear to impact short-term outcomes.

Clinical characteristics and outcomes in childhood-onset hypertrophic cardiomyopathy.

AIMS: Childhood-onset hypertrophic cardiomyopathy (HCM) is far less common than adult-onset disease, thus natural history is not well characterized. We aim to describe the characteristics and outcomes of childhood-onset HCM. METHODS AND RESULTS: We performed an observational cohort study of 7677 HCM patients from the Sarcomeric Human Cardiomyopathy Registry (SHaRe). Hypertrophic cardiomyopathy patients were stratified by age at diagnosis [<1 year (infancy), 1-18 years (childhood), >18 years (adulthood)] and assessed for composite endpoints reflecting heart failure (HF), life-threatening ventricular arrhythmias, atrial fibrillation (AF), and an overall composite that also included stroke and death. Stratifying by age of diagnosis, 184 (2.4%) patients were diagnosed in infancy; 1128 (14.7%) in childhood; and 6365 (82.9%) in adulthood. Childhood-onset HCM patients had an ∼2%/year event rate for the overall composite endpoint, with ventricular arrhythmias representing the most common event in the 1st decade following baseline visit, but HF and AF becoming more common by the end of the 2nd decade. Sarcomeric variants were more common in childhood-onset HCM (63%) and carried a worse prognosis than non-sarcomeric disease, including a greater than two-fold increased risk of HF [HRadj 2.39 (1.36-4.20), P = 0.003] and 67% increased risk of the overall composite outcome [HRadj 1.67 (1.16-2.41), P = 0.006]. When compared with adult-onset HCM, childhood-onset was 36% more likely to develop life-threatening ventricular arrhythmias [HRadj 1.36 (1.03-1.80)] and twice as likely to require transplant or ventricular assist device [HRadj 1.99 (1.23-3.23)]. CONCLUSION: Patients with childhood-onset HCM are more likely to have sarcomeric disease, carry a higher risk of life-threatening ventricular arrythmias, and have greater need for advanced HF therapies. These findings provide insight into the natural history of disease and can help inform clinical risk stratification.

Worldwide differences in primary prevention implantable cardioverter defibrillator utilization and outcomes in hypertrophic cardiomyopathy.

AIMS: Risk stratification algorithms for sudden cardiac death (SCD) in hypertrophic cardiomyopathy (HCM) and regional differences in clinical practice have evolved over time. We sought to compare primary prevention implantable cardioverter defibrillator (ICD) implantation rates and associated clinical outcomes in US vs. non-US tertiary HCM centres within the international Sarcomeric Human Cardiomyopathy Registry. METHODS AND RESULTS: We included patients with HCM enrolled from eight US sites (n = 2650) and five non-US (n = 2660) sites and used multivariable Cox-proportional hazards models to compare outcomes between sites. Primary prevention ICD implantation rates in US sites were two-fold higher than non-US sites (hazard ratio (HR) 2.27 [1.89-2.74]), including in individuals deemed at high 5-year SCD risk (≥6%) based on the HCM risk-SCD score (HR 3.27 [1.76-6.05]). US ICD recipients also had fewer traditional SCD risk factors. Among ICD recipients, rates of appropriate ICD therapy were significantly lower in US vs. non-US sites (HR 0.52 [0.28-0.97]). No significant difference was identified in the incidence of SCD/resuscitated cardiac arrest among non-recipients of ICDs in US vs. non-US sites (HR 1.21 [0.74-1.97]). CONCLUSION: Primary prevention ICDs are implanted more frequently in patients with HCM in US vs. non-US sites across the spectrum of SCD risk. There was a lower rate of appropriate ICD therapy in US sites, consistent with a lower-risk population, and no significant difference in SCD in US vs. non-US patients who did not receive an ICD. Further studies are needed to understand what drives malignant arrhythmias, optimize ICD allocation, and examine the impact of different ICD utilization strategies on long-term outcomes in HCM.

Asymmetric septal edema masking as hypertrophy in an infant with COVID-19 myocarditis.

Cardiac disease in pediatric patients due to coronavirus SARS-CoV-2 disease (COVID-19) includes myocarditis and multisystem inflammatory syndrome, both of which can present with a broad range in severity. Here we describe an infant with COVID-19 causing fulminant myocarditis with inotrope-resistant acute heart failure requiring extracorporeal membrane oxygenation. The patient demonstrated an atypical finding of localized septal thickening suggestive of hypertrophic cardiomyopathy, but the diagnosis of myocarditis was confirmed by cardiac MRI. Serial echocardiography illustrated complete resolution of septal hypertrophy and normalized cardiac function. The current report highlights the potential severity of COVID-19 associated myocarditis, the potential for recovery, and the utility of cardiac MRI in confirming the mechanism.

A Validated Model for Sudden Cardiac Death Risk Prediction in Pediatric Hypertrophic Cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy is the leading cause of sudden cardiac death (SCD) in children and young adults. Our objective was to develop and validate a SCD risk prediction model in pediatric hypertrophic cardiomyopathy to guide SCD prevention strategies. METHODS: In an international multicenter observational cohort study, phenotype-positive patients with isolated hypertrophic cardiomyopathy <18 years of age at diagnosis were eligible. The primary outcome variable was the time from diagnosis to a composite of SCD events at 5-year follow-up: SCD, resuscitated sudden cardiac arrest, and aborted SCD, that is, appropriate shock following primary prevention implantable cardioverter defibrillators. Competing risk models with cause-specific hazard regression were used to identify and quantify clinical and genetic factors associated with SCD. The cause-specific regression model was implemented using boosting, and tuned with 10 repeated 4-fold cross-validations. The final model was fitted using all data with the tuned hyperparameter value that maximizes the c-statistic, and its performance was characterized by using the c-statistic for competing risk models. The final model was validated in an independent external cohort (SHaRe [Sarcomeric Human Cardiomyopathy Registry], n=285). RESULTS: Overall, 572 patients met eligibility criteria with 2855 patient-years of follow-up. The 5-year cumulative proportion of SCD events was 9.1% (14 SCD, 25 resuscitated sudden cardiac arrests, and 14 aborted SCD). Risk predictors included age at diagnosis, documented nonsustained ventricular tachycardia, unexplained syncope, septal diameter z-score, left ventricular posterior wall diameter z score, left atrial diameter z score, peak left ventricular outflow tract gradient, and presence of a pathogenic variant. Unlike in adults, left ventricular outflow tract gradient had an inverse association, and family history of SCD had no association with SCD. Clinical and clinical/genetic models were developed to predict 5-year freedom from SCD. Both models adequately discriminated between patients with and without SCD events with a c-statistic of 0.75 and 0.76, respectively, and demonstrated good agreement between predicted and observed events in the primary and validation cohorts (validation c-statistic 0.71 and 0.72, respectively). CONCLUSION: Our study provides a validated SCD risk prediction model with >70% prediction accuracy and incorporates risk factors that are unique to pediatric hypertrophic cardiomyopathy. An individualized risk prediction model has the potential to improve the application of clinical practice guidelines and shared decision making for implantable cardioverter defibrillator insertion. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT0403679.

Mental health disorders and emergency resource use and outcomes in ventricular assist device supported patients.

There are limited data describing the prevalence of mental health disorders (MHDOs) in patients with ventricular assist devices (VADs), or associations between MHDOs and resource use or outcomes. We used the Nationwide Emergency Department Sample administrative database to analyze 44,041 ED encounters for VAD-supported adults from 2010 to 2017, to assess the relationship between MHDOs and outcomes in this population. MHDO diagnoses were present for 23% of encounters, and were associated with higher charges and rates of admission, but lower mortality.