BACKGROUND:Massive left ventricular hypertrophy (LVH) is a risk factor for sudden cardiac death in children with hypertrophic cardiomyopathy (HCM), but little is understood about its natural history. METHODS:Patients with pediatric-onset HCM identified from 2 registries (SHaRe [Sarcomeric Human Cardiomyopathy Registry] and IPHCC [International Paediatric Hypertrophic Cardiomyopathy Consortium]) with or without massive LVH were compared. Massive LVH was defined as absolute maximal left ventricular wall thickness (MLVWT) ≥30 mm or MLVWT z score ≥+20 at <18 years of age. Data from SHaRe and IPHCC include encounters from January 1960 through March 2024 and January 1970 through March 2024, respectively. Demographic, clinical, and serial MLVWT data were collected. Composite outcomes included major ventricular arrhythmia event (sudden cardiac death, aborted sudden cardiac death, or appropriate implantable cardioverter defibrillator therapy); heart failure (HF) event (left ventricular ejection fraction <50%, New York Heart Association class III or IV, transplant, or HF-related death); major adverse cardiac event (stroke or any major ventricular arrhythmia or HF outcome aside from left ventricular ejection fraction <50%); and HCM-related mortality (sudden cardiac death or HF-related death). Time-to-event analyses were performed using Cox proportional hazards models. RESULTS:We identified 587 patients (54 female [30%]). In 186 children with massive LVH, age at diagnosis was younger (median, 9.2 years [interquartile range, 2.1-13.1 years]) versus 13.6 years (9.7-15.5 years; P<0.001) and sarcomeric genetic variants more prevalent (72% versus 61%; P=0.034), as was HCM-related mortality (unadjusted hazard ratio, 3.3 [95% CI,1.2-9.7]; P=0.026), major adverse cardiac events (hazard ratio, 2.6 [1.7-3.9]; P<0.001), major ventricular arrhythmia (hazard ratio, 3.1 [1.8-5.2]; P<0.001), and HF (hazard ratio, 1.9 [1.1-3.1]; P=0.013). These associations remained significant when adjusted for sex and age at HCM diagnosis. In 115 patients with massive LVH with serial MLVWT data (62%), MLVWT increased significantly from first to last measurements (median, 26 mm [interquartile range, 18-32 mm] versus 31 mm [26-35 mm]; P<0.001), but there was no difference between z scores (median, +22 [interquartile range, +18 to +26] versus +23 [+20 to +28]; P=0.25). The last absolute MLVWT recorded was >5 mm less than the largest recorded MLVWT in 25 patients (22%). CONCLUSIONS:In pediatric HCM, massive LVH disproportionately affects those diagnosed in early childhood with sarcomeric disease, with increased risk for adverse events. Significant MLVWT regression is seen in nearly a quarter of patients.

Background: Genetic testing is a Class I recommendation for patients with hypertrophic cardiomyopathy (HCM). Variant classification relies on evidence from publicly available case data, evolving classification rules, and gene-disease associations. Thus, as knowledge increases, genetic variant classifications change over time. We evaluated the occurrence and reasons for variant reclassification from a large multi-center international HCM registry (Sarcomeric Human Cardiomyopathy Registry; SHaRe), with the goal to minimize uncertainty for patients and clinicians. Methods: Participants receive clinical care at specialized HCM centres. Baseline classifications were derived from the clinical genetic test report (original or updated) or prior further adjudication by SHaRe geneticists. All variants were then computationally reannotated and reevaluated during 2024-2025. Variants underwent expedited curation if no new evidence was present. The remainder underwent full manual curation using accepted criteria and classified as pathogenic/likely pathogenic (P/LP), variant of uncertain significance (VUS) and benign/likely benign (B/LB). VUS were sub-classified to high, mid or low. Results: Of 12,187 HCM patients, 8,054 (66%) had genetic testing between 1990-2024, and 4,923 (61%) had a variant identified in one of 29 ClinGen-validated HCM genes (1606 unique variants). Expedited curation was performed for 704 (44%) variants and 902 (56%) underwent manual curation. There were 1279 (79%) variants that retained their classification: 148 B/LB, 663 VUS, and 468 P/LP. While 276 (17%) variants (n=557 patients) were reclassified, including 73 upgrades: 61 from VUS to P/LP (199 patients), and 12 from B/LB to VUS. There were 203 downgrades: 108 from P/LP to VUS (196 patients), and 95 from P/LP or VUS to B/LB. VUS were additionally subclassified: 90 VUS-High, 129 VUS-Mid, 115 VUS-Low. Sub-classification of VUS resulted in less uncertainty, with 369 (40.6%) variants reclassified as VUS-Low or B/LB, indicating a very strong probability of not being HCM associated. Conclusions: Clinically meaningful reclassification occurred in 10% of variants identified in HCM probands. Most VUS were unlikely to be causal, and sub-classification has potential to reduce their burden on clinicians and families. Contemporary approaches to classification can minimize uncertainty of genetic results and highlight the need for periodic reevaluation. ### Competing Interest Statement SHaRe is supported by unrestricted funding from Bristol Myers Squibb, Cytokinetics, Alexion, and Lexicon. The sponsors had no role in the study design, data collection, data analysis, data interpretation, manuscript preparation, or the decision to submit the manuscript for publication. Dr. Ho is a consultant for or receives research funding from Bristol Myers Squibb, Pfizer, Cytokinetics, Tenaya, Biomarin, viz.AI, and Lexicon. Dr. Lakdawala recieves personal fees from Bridge Bio, Alexion, Tenaya, Cytokinetics, Bayer, and Gemma and grants from Bristol Myers Squibb and Pfizer. Dr. Owens consults for Avidity, Alexion, Bristol Myers Squibb, Bayer, Cytokinetics, Bridgebio, Braveheart, Edgewise, Imbria, Kardigan, Lexeo, Stealth, and Tenaya. Dr. Helms receives grants from Tenaya Therapeutics and Preload Therapeutics and personal fees from Lexeo Therapeutics, Preload Therapeutics, and Cytokinetics. Dr. Saberi receives grants from Bristol Myers Squibb during the conduct of the study as well as personal fees from Bristol Myers Squibb and Cytokinetics and grants from Cytokinetics, Lexicon, Edgewise, and Novartis. Dr. Parikh receives scientific advisory fees from Lexeo Therapeutics, Solid Biosciences, Constantiam Biosciences, Borrealis, and BioMarin. Dr. Ashley reported other from Personalis (founder and publicly traded stock), DeepCell (founder), Svexa (founder), Saturnus Bio (founder), Swift Bio (founder), Candela (founder, advisor), Parameter Health (founder, advisor), Pacific Biosciences (advisor, publicly traded stocks, collaborative support in kind), AstraZeneca (nonexecutive director, publicly traded stock), Dexcom (nonexecutive director), Illumina (collaborative support in kind), Oxford Nanopore (collaborative support in kind). Dr. Gray has received advisory board and education honoraria from Bristol Myers Squibb. Dr. Olivotto is a consultant for Bristol Myers Squibb, Cytokinetics, Tenaya, Lexeo, Edgewise, and Rocket Pharma. Dr. Michels is a consultant or receives research funding from Bristol Myers Squibb, Cytokinetics, Bayer, Alnylam, Biomarin, and Sanofi. Dr. Ware has consulted for MyoKardia (now Bristol Myers Squibb), Foresite Labs, and Pfizer. Dr. Crotti has consulted for Bristol Myers Squibb. Dr. Bundgaard receives lecture fees from Amgen, MSD, Sanofi, Bristol Myers Squibb, and Pfizer. Dr. Rossano is a consultant for AskBio, Astellas, CRI Biotech, Bristol Myers Squibb, Bayer, and Merck. Dr. Abrams is a consultant for Dinaqor. Dr. Maurizi has received grants from Bristol Meier Squibb, Amicus, Foundation CVCL, AICARM APS Onlus, Bangarter-Rhyner Foundation and fees (honoraria or consulting) from Bristol Meier Squibb and Academic CM. Dr. Thompson receives compensation as editor for Merck Manuals. Dr. Day receives personal fees from Lexicon Pharmaceuticals and Cytokinetics and grants from Bristol Myers Squibb. Disclosures are unrelated to current manuscript. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Each participating site has received ethics approval in accordance with local policies as per the following: ethical approval requiring informed consent was obtained from Cincinnati Childrens Hospital USA; Childrens Hospital of Philadelphia USA; Michigan Medical USA; Yale Medical USA; Royal Brompton Hospital United Kingdom; Erasmus University Medical Center The Netherlands; Florence Centre for Cardiomyopathies Italy; Sydney Local Health District Royal Prince Alfred Hospital Australia; and InCor Heart Institute University of Sao Paulo Brazil ethics committees. Waiver of consent was granted by Stanford School of Medicine USA; Brigham and Womens Hospital USA; Boston Childrens Hospital USA; Pennsylvania University Medical Center USA and Sydney Local Health District Royal Prince Alfred Hospital Australia ethics committees. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors Australian Government, https://ror.org/0314h5y94 Bristol-Myers Squibb (United States), https://ror.org/00gtmwv55 Cytokinetics (United States), https://ror.org/03tx9ss94 Alexion Pharmaceuticals (United States), https://ror.org/031ywxc85 Lexicon Pharmaceuticals (United States), https://ror.org/00v64s089

Long-term glucocorticoid therapy is the mainstay of treatment for individuals with Duchenne muscular dystrophy (DMD) but confers significant side effects. Vamorolone, a novel dissociative glucocorticoid for DMD, has similar anti-inflammatory effects on muscle, while sparing some adverse effects. It causes adrenal suppression but uniquely acts as a mineralocorticoid antagonist.We report a patient with DMD who switched from daily deflazacort to vamorolone at age 13.0 years. Six months later, he developed fever, vomiting, and diarrhea, necessitating oral hydrocortisone stress dosing. He presented to hospital, where he was hypotensive, hyponatremic (119 mmol/L), and mildly hyperkalemic. He received 3 days of intravenous hydrocortisone and fluids. Lisinopril and spironolactone were withheld.This case raised concern for an adrenal crisis, manifested by mineralocorticoid deficiency. It highlights the importance of stress dosing and checking electrolytes during illness when on vamorolone, especially if on cardiac medications, and education of patients, families, and multidisciplinary healthcare providers.

BACKGROUND:Patients with phenotypically mild hypertrophic cardiomyopathy (HCM) do not require symptom management, but may be at an earlier stage in the disease course, with potential to benefit from disease-modifying therapies. However, little is known about the natural history and predictors of major adverse cardiovascular events (MACE). OBJECTIVES:Using the Sarcomeric Human Cardiomyopathy Registry, we identified predictors of incident MACE and characterized disease progression in phenotypically mild HCM. METHODS:Phenotypically mild HCM was defined as: having shorter disease duration (<10 years since diagnosis or age ≤30 years), no previous MACE, being NYHA functional class I, and having a left ventricular (LV) maximal wall thickness (MWT) <25 mm. These individuals were followed prospectively for the development of symptoms or MACE: atrial fibrillation (AF), malignant ventricular arrhythmia (MVA) (sudden cardiac death, resuscitated arrest, or appropriate defibrillator therapy), heart failure (HF) (cardiac transplantation, LV assist device implantation, LV ejection fraction <35%, or NYHA functional class III or IV symptoms), stroke, or all-cause mortality. Cox regression identified MACE predictors. Linear and latent class mixed models characterized LV remodeling trajectories and risk clusters. RESULTS:Of 2,500 participants with phenotypically mild HCM (mean age 43 years, 31% women) followed for a mean duration of 7 ± 6 years, 534 (21%) developed MACE, including 289 with AF, 69 with MVA, and 193 with HF. Individuals who progressed from NYHA functional class I to ≥ II symptoms during follow-up (n = 585, 23%) were 2.79 times (95% CI: 2.30-3.39 times) more likely to experience MACE. Age at baseline (HR: 1.24; 95% CI: 1.17-1.32 per 10-year increase), body mass index (HR: 1.10; 95% CI: 1.01-1.21 per 5-kg/m2 increase), left atrial (LA) diameter (HR: 1.16; 95% CI: 1.09-1.25 per 5-mm increase), LV MWT (HR: 1.27; 95% CI: 1.10-1.46 per 5-mm increase), and LV outflow tract (LVOT) gradient (HR: 1.08; 95% CI: 1.05-1.12 per 15-mm Hg increase) associated with higher MACE rates. LV late gadolinium enhancement presence was associated with 36% (95% CI: 5%-76%) higher hazard of MACE. Remodeling trajectories during follow-up predicted risk with each 0.5 mm/year steeper increase in LA diameter associating with doubled AF (HR: 2.24; 95% CI: 1.69-2.97) and HF rates (HR: 2.22; 95% CI: 1.62-3.04) and each 0.5 mm/year steeper LV MWT increase associating with doubled MVA rates (HR: 1.92; 95% CI: 1.38-2.69). Higher sustained values and/or steeper increases in LA diameter, LV MWT, or LVOT gradient associated with the highest MACE rates. CONCLUSIONS:Approximately 21% of patients with phenotypically mild HCM developed MACE over medium-term follow-up. Older age, symptoms development, and increasing LA diameter, LV hypertrophy, or LVOT gradient associated with MACE, particularly in instances of steeper rate of change. These findings can guide management strategies and inform future studies of disease-modifying therapies.

Neonatal heart failure is a clinical syndrome caused by cardiovascular and noncardiovascular abnormalities, which results in characteristic signs and symptoms including edema, respiratory distress, and growth failure accompanied by circulatory, neurohormonal, and molecular derangements. The causes of neonatal heart failure are varied and include congenital heart disease, inherited or acquired cardiomyopathy, and systemic diseases. Accurate diagnosis of etiology is key for appropriate therapy and is comprised of thorough evaluation, including family history, focused physical exam, noninvasive cardiac testing, laboratory testing, and, in appropriate cases, invasive testing including endomyocardial biopsy. Treatment options include diuretic therapy, afterload reduction, beta-blockade, inotropic and vasoactive medications, mechanical ventilatory and circulatory support, and heart transplantation. In the majority of instances, these treatment modalities have been described in adult or older pediatric populations and can only be extrapolated to the neonatal age-group.

BACKGROUND/OBJECTIVES:Outcomes for pediatric relapsed/refractory (R/R) acute myeloid leukemia (AML) remain dismal. CPX-351, a liposomal formulation of cytarabine and daunorubicin, may have less off-target toxicities than traditional chemotherapies and has shown improved outcomes for adults with newly diagnosed therapy-related AML. DESIGN/METHODS:In this first-in-pediatric, single center phase 1 study (NCT01943682), 27 patients with R/R acute leukemia (acute lymphoblastic leukemia [ALL, n = 3], AML [n = 23], or mixed phenotype acute leukemia [MPAL, n = 1]) received one cycle of CPX-351 (on days 1, 3, 5) at either 44 mg/m2 daunorubicin/dose or 59 mg/m2 daunorubicin/dose. The primary objectives were to determine the CPX-351 recommended phase 2 dose (RP2D) and to evaluate its tolerability; secondary objectives were to assess marrow overall response rate (ORR) and cardiotoxicity. RESULTS:The RP2D was determined to be 44 mg/m2 daunorubicin/dose. Grade ≥3 non-hematologic toxicities occurred in 89% of patients including febrile neutropenia (85%), infection (52%), and maculo-papular rash (37%). No grade ≥3 acute cardiac toxicities or significant changes in cardiac biomarkers were detected. The marrow ORR for AML patients was 48% (10/21 evaluable patients), despite high-risk genetic findings in most and nearly half of patients having undergone prior hematopoietic stem cell transplant. No patients with ALL or MPAL responded. CONCLUSION:CPX-351 at 44 mg/m2 daunorubicin/dose was safe and tolerable in children with R/R acute leukemia, showing promising activity in heavily pretreated, high-risk AML and is now the FDA-approved pediatric dose for therapy-related AML or AML with myelodysplastic changes.

BACKGROUND:Sarcomere gene variants are a key cause of hypertrophic cardiomyopathy (HCM), and have been associated with worse prognosis. However, it is unclear how comorbidities influence clinical trajectories, the timing of events, and causes of death in sarcomeric and nonsarcomeric HCM. METHODS:We conducted a multicenter longitudinal cohort study of genotyped patients with HCM in the Sarcomeric Human Cardiomyopathy registry (SHaRe). Patients were classified as sarcomeric HCM (pathogenic/likely pathogenic sarcomere variant) or nonsarcomeric HCM (genetically elusive). The influence of genetic classification and comorbidities on the sequence of cardiovascular events were assessed in time-varying Cox proportional hazards models. RESULTS:Among 6120 patients (40% women; 87% probands; 50% sarcomeric HCM), followed for a median of 5.3 years, sarcomeric HCM (n=3082) was associated with a younger age at diagnosis (median 38.1 versus 54.3 years; P<0.001), a higher proportion of women and less obesity, hypertension, and left ventricular (LV) obstruction. After age standardization, sarcomeric HCM was associated with a higher burden of atrial fibrillation (age-standardized incidence [ASI] ratio, 1.28 [CI, 1.16-1.40]), LV systolic dysfunction (ASI ratio, 1.31 [CI, 1.15-1.48]), and ventricular arrhythmias (ASI ratio, 1.37 [CI, 1.17-1.52]) than nonsarcomeric HCM. All-cause mortality was similar (10.4% versus 9.4%; P=0.20); however, patients with sarcomeric HCM died younger (mean 7.8 years; P<0.001), with model-based survival-analysis estimating 3.5 life-years lost between ages 44 and 85. Sarcomeric HCM was also associated with higher HCM-related mortality (hazard ratio [HR], 1.61 [CI, 1.18-2.20]). Temporal analysis identified atrial fibrillation as the strongest disease-modifier, increasing the risk of LV systolic dysfunction (HR, 2.54 [CI 2.07-3.11]), ventricular arrhythmias (HR, 3.13 [CI, 2.36-4.20]), and mortality (HR, 1.94 [CI, 1.64-2.31]) in both groups. Genotype-interaction analyses demonstrated a larger impact of atrial fibrillation and LV systolic dysfunction on adverse outcomes in sarcomeric versus nonsarcomeric HCM, with effect ratios up to 1.98 for severe heart failure and 2.01 for mortality (both P<0.01). CONCLUSIONS:Genotype can refine risk stratification and inform clinical management in HCM. Sarcomeric HCM is associated with worse prognosis and may benefit from more vigilant surveillance for arrhythmias and systolic dysfunction, with a lower threshold for advanced therapies. Comorbidities, including hypertension and obesity, may be modifiable risk factors for patients with nonsarcomeric HCM.

Childhood cancer survivors (CCS) are at elevated risk for cardiovascular disease due to cardiotoxic cancer therapies. Different international guidelines and recommendations for follow-up were published. However, global practices surrounding cardiovascular risk assessment, screening, and management in CCS remain variable and incompletely characterized. A 20-question survey was created by the Pediatric Working Group of the International Cardio-Oncology Society (ICOS) for medical practitioners involved in the care of CCS to assess current practices in cardiovascular risk evaluation, preventive strategies, screening modalities, cardiology referral, and heart failure (HF) management. The survey distribution was a collaborative effort by ICOS pediatric work group leaders. Descriptive statistics were used to summarize responses. A total of 123 unique practitioners responded, with 75

We describe the epidemiology of invasive fungal disease (IFD) in pediatric heart transplant recipients. Eight patients (4%) suffered IFD. Prolonged central access, delayed chest closure, broad-spectrum antibiotics, and extracorporeal membrane oxygenation (ECMO) were associated with early post-transplant IFD. Delayed chest closure and ECMO were associated with administration of systemic antifungals.

Introduction: Sodium-glucose cotransporter 2 inhibitors (SGLT2is) are utilized in pediatric heart failure (HF) with little data on dosing or safety profile. Our aim is to report on dosing and adverse events associated with SGLT2i use in pediatric HF. Methods: A retrospective study was performed utilizing the Advanced Cardiac Therapies Improving Outcomes Network (ACTION) pediatric heart failure registry. Patient demographics, medical regimen, echocardiographic data, laboratory data, adverse events, and relevant heart failure outcomes were collected at SGLT2i initiation and last follow-up. Results: At time of database query, data from 278 patients from 19 institutions were common. The most common SGLT2i prescribed was dapagliflozin (244) followed by empagliflozin (34). Median age at initiation was 15.1 years (IQR 10.7–18.2), 106 had DCM, 54 had Fontan physiology, and 67

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

The calcium/calmodulin-dependent protein kinase type 2 (CAMK2) family consists of four different isozymes, encoded by four different genes-CAMK2A, CAMK2B, CAMK2G, and CAMK2D-of which the first three have been associated recently with neurodevelopmental disorders. CAMK2D is one of the major CAMK2 proteins expressed in the heart and has been associated with cardiac anomalies. Although this CAMK2 isoform is also known to be one of the major CAMK2 subtypes expressed during early brain development, it has never been linked with neurodevelopmental disorders until now. Here we show that CAMK2D plays an important role in neurodevelopment not only in mice but also in humans. We identified eight individuals harboring heterozygous variants in CAMK2D who display symptoms of intellectual disability, delayed speech, behavioral problems, and dilated cardiomyopathy. The majority of the variants tested lead to a gain of function (GoF), which appears to cause both neurological problems and dilated cardiomyopathy. In contrast, loss-of-function (LoF) variants appear to induce only neurological symptoms. Together, we describe a cohort of individuals with neurodevelopmental disorders and cardiac anomalies, harboring pathogenic variants in CAMK2D, confirming an important role for the CAMK2D isozyme in both heart and brain function.

BACKGROUND:Duchenne muscular dystrophy (DMD) has unique characteristics when compared with other forms of non-DMD dilated cardiomyopathy. We sought to describe epicardial adipose tissue (EAT), the fat layer surrounding the myocardium, and investigate its relationship to longitudinal cardiac changes in DMD. METHODS:This single-center, retrospective, cohort study included all DMD patients with ≥5 cardiac magnetic resonance studies between 2015 and 2022. EAT thickness was measured in the right atrioventricular groove during end diastole. Adiposity data were obtained from dual-energy x-ray absorptiometry scans. Linear mixed-effects regression was used for statistical modeling. RESULTS:A total of 117 patients were included with 590 cardiac magnetic resonance studies, 333 dual-energy X-ray absorptiometry, and 255 NT-proBNP (N-terminal pro-B-type natriuretic peptide) values. The median age at first cardiac magnetic resonance was 13.1 years and at any cardiac magnetic resonance study was 15.9 years. The median EAT thickness was 15.5±4 mm. EAT thickness was positively associated with age (P<0.001) and measures of general adiposity (P<0.01). Increased EAT was positively associated with NT-proBNP and negatively associated with left ventricular volume and left ventricular mass indexed for body surface area (P<0.05). There was no association with left ventricular ejection fraction (P=0.98) or for left ventricular volume (P=0.61) or mass (P=0.52) when indexed for height. CONCLUSIONS:DMD is associated with early, appreciable EAT, which increases over the life span and is positively related to measures of general adiposity. Increased EAT is associated with higher levels of NT-proBNP without a change in systolic function, suggesting it may contribute to diastolic dysfunction in DMD.