BACKGROUND:Although genotype-based risk stratification for aortic disease has been extensively studied in Marfan syndrome (MFS), mitral valve disease has received less attention despite being a major cardiovascular complication requiring surgery in up to 16% of cases. OBJECTIVES:The authors aimed to evaluate genotype-specific differences in mitral valve disease progression and surgical intervention to inform precision medicine approaches in MFS. METHODS:This retrospective cohort study included 437 MFS patients with pathogenic FBN1 variants (2006-2024). Variants were classified by molecular mechanism (premature termination codon [PTC] variants vs in-frame variants [IFVs]) and genomic location. Time-to-event cause-specific analysis assessed genotype-specific risks for mitral valve surgery. RESULTS:Among 437 patients, 206 (47.1%) had PTC variants and 231 (52.9%) IFVs. Mitral valve surgery was performed in 38 patients (8.7%) at median age of 25.0 years. Among IFVs, those within the DNCD region (Dominant Negative variants affecting Cysteine residues and in-frame Deletions; exons 26-37 and 44-50) showed markedly higher 30-year cumulative incidence of mitral valve surgery (23.8% [95% CI: 11.7%-35.9%] vs 1.24% [95% CI: 0.0%-2.96%] in other IFVs and 3.20% [95% CI: 0.66%-5.77%] in PTC variants). IFVs within the DNCD region showed the earliest onset of mitral valve surgery in childhood/adolescence, whereas PTC variants demonstrated delayed risk beginning around age 30 years. Cox analysis confirmed IFVs within the DNCD region had highest risk of mitral valve surgery for patients aged ≤30 years (HR: 7.83 vs PTC variants; 95% CI: 3.14-19.57; P < 0.001) with robust discrimination (C-index = 0.725). CONCLUSIONS:IFVs within the DNCD region confer the highest risk for mitral valve surgery with distinct age-dependent patterns. These findings enable genotype-guided risk stratification with age-specific surveillance protocols, potentially transforming clinical management in MFS.

Background:Pulmonary arterial hypertension (PAH) is characterized by a progressive increase in pulmonary arterial pressure (PAP) and pulmonary vascular resistance (PVR), imposing an increased workload on the right ventricle and ultimately leading to right heart failure. Macitentan is a potent dual endothelin receptor antagonist that blocks both endothelin receptor subtypes A and B, and is approved for adult patients with PAH, but evidence in pediatric PAH patients is limited. Methods and Results:This was an open-label, multicenter, Phase III study enrolling Japanese pediatric PAH patients aged ≥3 months to <15 years. A total of 7 patients were enrolled. Efficacy was evaluated by assessing pulmonary hemodynamics after 24 weeks of treatment, and safety was assessed over a 52-week period. The geometric mean fold change in PVR index (PVRI) at Week 24 was 59.43%, which met the prespecified success criterion of ≤81.6% (primary endpoint). Other pulmonary hemodynamic parameters, including mean PAP, mean right atrial pressure, and total pulmonary resistance, also showed improvement. Additionally, at Week 52, functional outcomes such as 6-minute walk test performance and quality-of-life reports, demonstrated a trend toward improvement. Safety findings were favorable, with no unexpected concerns among the 7 treated participants. Most adverse events were mild to moderate in severity, and none were considered related to macitentan. Conclusions:Macitentan showed clinically meaningful reduction in PVRI and improved pulmonary hemodynamics in Japanese pediatric patients with PAH, with a favorable safety profile over 52 weeks of treatment.

FUZ, a component of the CPLANE (ciliogenesis and planar polarity effector) complex, regulates primary ciliogenesis. Five patients of various types of skeletal dysplasia with biallelic FUZ variants have been reported to date, yet the gene-disease relationship has not been established. Here, we report a patient with ciliopathy with a novel homozygous missense variant in FUZ. This patient shares phenotypes with all the previously reported patients and presents with novel phenotypes: aorto-pulmonary window (AP window) and Hirschsprung disease. These phenotypes can be explained by the inhibition of neural crest cell migration due to abnormal Sonic hedgehog (Shh) signaling caused by primary cilia dysfunction. In silico three-dimensional structural analysis predicted that the variant alters interactions between FUZ and CPLANE2 (RSG1), potentially disrupting ciliogenesis. This report provides additional evidence for FUZ as a causative gene for ciliopathy, offering novel insights into the phenotype spectrum and molecular mechanisms of FUZ-related ciliopathy.

BACKGROUND:Although surgery was traditionally the primary modality for definitive patent ductus arteriosus (PDA) closure, the indications for transcatheter closure have expanded with device advancements in recent decades. This study aimed to describe the trends in surgical and transcatheter closure for PDA in Japan. METHODS:Patients aged <16 years who underwent procedural PDA closure between April 2011 and March 2023 were identified from the Diagnosis Procedure Combination database in Japan. Considering the redaction of the requirements for the Amplatzer Duct Occluder (age ≥6 months and weight ≥6 kg) in 2016, patients were stratified by this erstwhile weight threshold (6 kg) to evaluate the impact of this regulatory change. We analyzed data from consecutive 2-year periods. We examined the trend in the proportion of transcatheter closure among all procedural PDA closures using multivariable mixed-effects logistic regression models. RESULTS:The study enrolled 5638 patients (3235 weighing <6 kg and 2403 weighing ≥6 kg). The proportion of transcatheter closure increased over time from 13/466 (2.8%) patients in 2011-2012 to 60/431 (13.9%) in 2021-2022 in patients weighing <6 kg (adjusted odds ratio 1.46, 95% confidence interval 1.29-1.67), and from 268/316 (84.8%; 2011-2012) to 392/416 (94.2%; 2021-2022) in patients weighing ≥6 kg (1.56, 1.38-1.76). CONCLUSIONS:Although the proportion of transcatheter closure steadily increased in patients weighing <6 kg, its implementation was slow and surgical closure remained the primary treatment. Transcatheter closure has become the predominant option for patients weighing ≥6 kg.

Bone mineral density (BMD) in pediatric Marfan syndrome (MFS) patients remains debated. While dual X-ray absorptiometry for BMD assessment is gold standard, it is unreliable in scoliosis. Hounsfield Units (HU) measurement from lumbar CT scans in pediatric patients is increasingly used. The aim of this study is to evaluate BMD in patients with MFS by comparing HU values with those of adolescent idiopathic scoliosis (AIS) patients scheduled for spinal correction surgery. Propensity score matching (1:2, ages 10–19) was performed between MFS and AIS patients based on age, sex, body mass index (BMI), and spinal deformity severity. HU values were measured at L1, L3, and L5 on middle axial CT images using reconstruction software, excluding posterior vertebral body radiolucency. Medication histories were recorded. From 33 MFS and 209 AIS patients undergoing posterior fusion (2007–2024), 31 MFS patients were matched 1:2 with 62 AIS controls. One MFS patient had used progesterone before CT. HU values were significantly lower in MFS than AIS at each vertebra; average HU was 168.7 vs. 214.0 (P < 0.001). In MFS patients, low HU values were associated with low BMI, large Cobb angle, and prior angiotensin receptor blocker use. No patients in either group received vitamin D or other bone-related treatments. While routine CT is discouraged to minimize radiation, utilizing existing preoperative data for opportunistic bone screening may be considered for pediatric MFS patients, given the high prevalence of values below the osteoporotic threshold.

BACKGROUND:Visual assessment of membrane motion is essential for managing EXCOR VAD, but accuracy depends on observer experience. We evaluated a high-speed image AI model to support healthcare providers. METHODS:Patients on EXCOR Pediatric admitted to the University of Tokyo Hospital (May 2022-May 2024) were included. Membrane images were obtained from patients and a manually filled pump at bench. An image recognition model was trained to estimate membrane position. Experienced physicians (N = 11) and inexperienced physicians (N = 11) assessed pump status in a sample dataset (N = 12) with and without AI assistance. RESULTS:A total of 142 movies from five patients were collected (98 training, 45 validation), plus 1100 bench images for training. Model accuracy was 0.91, with AUROCs of 0.99 ("fill") and 0.96 ("empty"). Among experienced physicians, accuracy significantly improved with AI assistance from 0.83 (0.67-0.88) to 0.92 (0.92-1.0) (median (IQR); p = 0.016). Among inexperienced physicians, accuracy also significantly improved with AI assistance from 0.67 (0.5-0.75) to 0.83 (0.75-0.92) (p = 0.049). CONCLUSION:A high-speed image AI can facilitate the visual assessment of EXCOR VAD by healthcare providers.

Fontan-associated liver disease (FALD) is a progressive congestive hepatopathy that often leads to cirrhosis and hepatocellular carcinoma. Liver nodules are common in FALD; however, noninvasive predictors remain understudied. This study aimed to determine the prevalence and risk factors for liver nodule development in patients with Fontan circulation. This prospective single-center cohort study enrolled 198 post-Fontan patients (median age 17.3 years; median time since Fontan surgery 14.0 years) who underwent abdominal ultrasound and liver stiffness measurement (LSM) by transient elastography between January 2015 and June 2025. Cross-sectional analysis assessed baseline predictors of liver nodules. A longitudinal subset (n = 112) was followed for a mean of 3.8 years to identify predictors of liver nodule development. Abnormal ultrasonographic findings were detected in 90

Heritable thoracic aortic diseases (HTAD) are inherited conditions that increase the risk of thoracic aortic aneurysms, dissections, and premature aortic rupture. Advances in human genetics and experimental models have transformed our understanding of these disorders from a phenotype-based classification system to a mechanism-based view involving extracellular matrix (ECM) architecture, transforming growth factor-β (TGFβ) signaling, and vascular smooth muscle cell contractility. Marfan syndrome, Loeys-Dietz syndrome, and nonsyndromic HTAD demonstrate how genetic mutations can disrupt the components that stabilize the aortic wall. These pathogenic mechanisms influence matrix organization, intracellular signaling, and the contractile machinery within the mechanically stressed proximal aorta. In this review, we summarize current mechanistic insights into the major forms of HTAD and discuss how new molecular and cellular concepts could influence surveillance, genetic counseling, and genotype-guided therapeutic strategies.

BACKGROUND:Ventricular perforation is a serious complication of percutaneous myocardial biopsy. Accurate orientation of the biopsy forceps toward the ventricular septum under fluoroscopy is essential to minimise this risk. However, in paediatric patients, variations in ventricular septal orientation complicate proper forceps alignment. No previous studies have addressed this variability in children. METHODS:We retrospectively analysed paediatric patients who underwent myocardial biopsy between January 2019 and June 2023. The angle of the ventricular septum relative to the sagittal plane was measured using cardiac CT. Biopsies were performed under fluoroscopic guidance, with individualised angles adjusted to align with the septum. Fluoroscopic images were used to calculate the angle between the biopsy forceps and the septum and the combined angle relative to the sagittal plane. RESULTS:Sixteen patients underwent a total of 85 biopsies; only the first biopsy per patient was included in the analysis. The mean angle of the septum was 54.3° (range: 30.0-75.0°), the mean angle between forceps and septum was 21.3° (range: 3.5-53.4°), and the combined angle relative to the sagittal plane was 75.6° (range: 45.0-115.7°). No cases of ventricular perforation were observed. CONCLUSION:Ventricular septal orientation varies significantly in paediatric patients. Individualised adjustment of fluoroscopic angles based on pre-procedural CT measurements allows accurate positioning of biopsy forceps and may reduce the risk of severe complications.

Orthotopic heart transplantation after the Fontan operation presents technical surgical challenges due to the connection of systemic veins to pulmonary arteries and well-developed systemic-to-pulmonary collateral arteries. The altered anatomy and hemodynamics necessitate extensive vascular reconstruction. We report a successful orthotopic heart transplantation with three years of ventricular assist device (VAD) support in a child who had undergone the Fontan operation. A 10-year-old boy had undergone extracardiac total cavopulmonary connection (18 mm expanded polytetrafluoroethylene conduit) at 2 years of age for a large ventricular septal defect, straddling tricuspid valve, and mitral stenosis. Following the Fontan operation, his systemic ventricular function gradually deteriorated. At 7 years of age, a Berlin Heart EXCOR® Pediatric VAD was implanted due to progressive heart failure, and he was listed for heart transplantation. Three years later, a heart transplant was performed. Cardiopulmonary bypass was established via cervical cannulation before re-sternotomy. The superior vena cava and extracardiac conduit were detached from the pulmonary artery. The pulmonary artery was reconstructed from hilum to hilum with a large bovine pericardial patch. Well-developed systemic-to-pulmonary collaterals caused excessive left atrial return; therefore, the left atrial anastomosis was performed under deep hypothermic circulatory arrest. The systemic veins were reconstructed with bicaval anastomosis, and inferior vena caval continuity was restored by leaving a short segment of the previous conduit. The procedure was completed without complications. Postoperative recovery was uneventful, and the patient was discharged on day 35. This case illustrates a successful approach to orthotopic heart transplantation in a child with failing Fontan circulation supported by a VAD. Reconstruction of the pulmonary artery using a large pericardial patch and restoration of bicaval continuity were key to overcoming complex anatomical challenges.

Background: Pulmonary hypertension (PH) is a major determinant of outcomes in congenital heart disease (CHD), yet tools for individualized prognostic estimation are limited. This study aimed to develop an exploratory, clinically oriented prediction model for estimating cardiac event-free survival in patients with CHD-PH. Methods: Data from the nationwide Japanese Association of CHD-PH Registry were analyzed in a retrospective cohort derived from a prospectively maintained registry. Cardiac event-free survival was evaluated using Cox proportional hazards models incorporating prespecified, routinely available clinical and hemodynamic variables. Cardiac events were defined as death, transplantation, clinical worsening requiring treatment escalation, or PH-related hospitalization. Results: A total of 224 patients were included, and 23 experienced 29 cardiac events during a median follow-up of 1.5 years. These included 7 cardiovascular deaths, 1 lung transplantation, and 1 atrial septostomy, 13 cases of clinical worsening. The cardiac event-free survival rates were 94.0% and 86.2% at 1 and 2 years, respectively. In multivariable analysis, trisomy 21 (hazard ratio [HR] 3.63), elevated pulmonary vascular resistance index (PVRI; HR 13.2), and elevated central venous pressure (CVP; HR 3.27) were associated with worse outcomes. These associations were consistent in sensitivity and subgroup analyses. Model-based estimates demonstrated risk gradients across clinically relevant profiles and were incorporated into a prototype prediction tool. Conclusions: An exploratory pragmatic prediction model for cardiac event-free survival in CHD-PH was developed using nationwide registry data. These findings support the feasibility of a registry-based prognostic framework; however, further validation is required before clinical application.

Background:Transposition of the great arteries (TGA) with ventricular septal defect (VSD) and pulmonary stenosis (PS) presents complex hemodynamic challenges, frequently requiring staged palliative interventions. To inform optimal treatment strategies, we developed computational cardiovascular models to simulate the hemodynamics of TGA/VSD/PS. Methods:These models yielded critical hemodynamic parameters, including systemic oxygenation, pulmonary-to-systemic flow ratio (Qp/Qs), and mean pulmonary artery pressure (mPAP). By modulating resistances of the atrial septal defect (ASD), systemic-to-pulmonary shunt (SPS), and PS, we evaluated the impacts of diverse palliative interventions, such as ASD enlargement, SPS placement, and pulmonary artery banding (PAB). Results:Our model with severe PS revealed that a moderate or larger ASD or SPS is indispensable for achieving adequate blood mixing and systemic oxygenation. Both ASD enlargement and SPS placement enhanced oxygenation; however, ASD enlargement resulted in a smaller increase in Qp/Qs and a reduction in mPAP, fostering hemodynamic stability. The combined application of SPS and PAB demonstrated superior efficacy in reducing Qp/Qs and mPAP compared to SPS placement alone. The analysis of ASD flow patterns revealed that an inadequate ASD size accentuated the late component of ventricular systolic left-to-right flow (σ-wave), resulting in a square-shaped pattern, independent of SPS or PS. Echocardiographic flow patterns thus present a clinical reliable indicator of ASD adequacy beyond morphologic assessment. Conclusions:These findings support a palliative treatment strategy in which percutaneous ASD enlargement is prioritized, guided by echocardiographic ASD flow patterns. If adequate ASD enlargement cannot be achieved, SPS placement should be performed, with concomitant consideration of PAB.

Noonan syndrome is associated with lymphatic system structural abnormalities and may present with potentially fatal refractory chylothorax. We report a 2-year-old boy with Noonan syndrome with non-traumatic chylothorax who was refractory to dietary therapy with medium-chain triglyceride milk, octreotide, prednisolone, lymphatic embolisation, and lymphatico-venous anastomosis but improved with etilefrine administration. Etilefrine may be a treatment option for paediatric chylothorax, regardless of the aetiology.

BACKGROUND:Selexipag, an oral prostacyclin (PGI2) receptor agonist, is approved for adult patients with pulmonary arterial hypertension (PAH). This study evaluated the efficacy and safety of selexipag for Japanese pediatric patients with PAH. METHODS AND RESULTS:The study enrolled 6 patients who received selexipag twice daily at an individualized dose based on body weight; maintenance doses were determined for each patient by 12 weeks after starting administration. Efficacy, including pulmonary hemodynamics, was evaluated after 16 weeks, and efficacy and safety were further evaluated 52 weeks after treatment was initiated in the last enrolled patient. The mean (±SD) change in the pulmonary vascular resistance index from baseline to Week 16 (the primary endpoint of the study) was -5.55±6.88 Wood units·m2; improvements were also seen in other pulmonary hemodynamic parameters. The 6-min walk distance increased and N-terminal pro-B-type natriuretic peptide decreased up to Week 64, but the between-subject variability was large. The World Health Organization functional class was improved in 1 of 6 patients at Week 16 and in 2 of 4 patients at Week 64. No patient worsened. The major side effects of selexipag were those characteristic of PGI2, and the safety profile of selexipag was similar to that in adult patients. CONCLUSIONS:The efficacy and safety of selexipag in Japanese pediatric patients with PAH were demonstrated.

Infantile-onset restrictive cardiomyopathy (iRCM) is rare and is often associated with poor prognosis.1,2,3 As in adult-onset cases, variants in sarcomere genes, including MYH7, have been reported as causative mutations in patients with iRCM,2,3 but little is known about which variants cause earlier-onset and more severe phenotypes. In this report, we describe an iRCM patient with atrioventricular block (AVB) and right ventricle (RV) hypoplasia, who had a novel missense mutation in the MYH7 lever region. Among the various phenotypes of MYH7 mutations, this variant caused the most severe clinical course, which suggests that the region containing this variant plays an essential role in myosin function.

BACKGROUND:Stent implantation for vascular stenosis associated with congenital heart diseases is commonly performed as an off-label procedure in Japan because there is no officially approved stent for any congenital heart disease. METHODS AND RESULTS:We analyzed data from the Japanese Society of Congenital Interventional Cardiology Registry collected from January 2016 to December 2018. Patients who underwent stent implantation were enrolled in the present analysis. During the study period, there were 470 procedures, 443 sessions, and 391 cases. Of 443 sessions, 427 (96.4%) succeeded procedurally. There were no differences in the procedural success rates among age groups. In all, 416 sessions (367 patients; 94%) resulted in survival to 30 days after catheter intervention. Of 392 admissions, 357 patients (91%) survived to discharge. Only 4 deaths were directly related to stent implantation. Some in-hospital complications were observed during 55 of 443 sessions. Both hospital deaths and serious complications were significantly more frequent in the group with various preoperative risk factors. CONCLUSIONS:Although not officially approved for congenital heart diseases in Japan, stent implantation in congenital heart diseases has been widely and routinely performed for many years with safety and efficacy. The aim of stenting was variable and broad because of many different applications and morphological variations. These data may facilitate approval of such an important device in Japan.

Alagille syndrome is caused by mutations in genes involved in NOTCH signaling, specifically JAG1 and NOTCH2, and is associated with a high rate of peripheral pulmonary artery stenosis. In this study, we report the case of an infant with Alagille syndrome caused by a JAG1 mutation, who succumbed to acute exacerbation of right heart failure due to severe peripheral pulmonary artery stenosis. The autopsy revealed that the peripheral pulmonary arteries were significantly stenosed, exhibiting hypoplasia and thickened vessel walls. Histological examination of the pulmonary artery walls showed a decrease in smooth muscle cells in the tunica media and an increase in collagen and elastic fibers, although the intrapulmonary arteries were intact. These findings are important for understanding the pathogenesis of Alagille syndrome and developing treatment strategies for peripheral pulmonary artery stenosis.