Background: This nationwide survey investigated new heart failure drug prescriptions by Japanese pediatric cardiologists. Methods and Results: Among 97 responding institutions, 357 patients received sodium-glucose cotransporter-2 inhibitors (SGLT-2i; n=189), angiotensin receptor-neprilysin inhibitors (ARNI; n=89), selective hyperpolarization-activated cyclic nucleotide-gated channel (HCN) blockers (n=76), or soluble guanylate cyclase (sGC) stimulators (n=3). SGLT-2i were predominantly prescribed in post-Fontan patients (45%), with one-third being children under 18 years. ARNI were commonly used for biventricular congenital heart disease (CHD) and cardiomyopathy (47% and 29%), with 40% under 18 years. Conclusions: Pediatric-specific clinical trials and appropriate usage guidelines are urgently needed.

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:Clarifying clinical features of critically ill pediatric patients is essential for optimizing the regional emergency care system. However, the relationships between hospital case volume, interhospital transfer, and outcomes, including causes of death, remain unclear. METHODS:An observational study was conducted using prospectively collected data on critically ill patients aged 15 years or younger. Patients enrolled in this study were those who met the criteria for emergency and critical care unit management in Fukuoka Prefecture, Japan, from June 2014 to May 2019. Data on etiologic categories, outcomes, interhospital transfer, and use of intensive care interventions were collected. Hospitals were classified according to patient volume (high-volume: ≥ 100 and low-volume: < 100 patients during the observation period). RESULTS:Among 3124 patients, 891 (28.5%) were infants (< 1 year). The annual incidence was 0.85 per 1000 children. Endogenous, exogenous, and "undetermined" etiologies accounted for 2481 (79.4%), 495 (15.8%), and 148 (4.7%) patients, respectively. Of 327 deaths (10.5%), 157 (48.0%) occurred in infants, and 89 (56.7%) of infant deaths were classified as "undetermined". In-hospital mortality among admitted patients was higher in low-volume hospitals (8.7% vs. 5.3%, p < 0.01), as was the proportion of "undetermined" deaths (49.5% vs. 28.8%, p < 0.01). Transferred patients had higher ICU admission rates (62.5% vs. 52.6%, p < 0.01), without higher mortality among admitted patients. CONCLUSIONS:Critically ill infants had high mortality, and many deaths remained undetermined. These findings highlight the need to strengthen regional transport systems and postmortem evaluation in pediatric emergency care.

BACKGROUND:Children with right isomerism usually accompany complex congenital heart disease, which is associated with pulmonary atresia, common atrioventricular valve, and total anomalous pulmonary venous connection. This study aimed to explore specific cardiovascular morphology associated with right isomerism on computed tomography angiography (CTA). METHODS:We retrospectively reviewed CTA images to assess the atrio-ventricular connections and the spatial relationship between the systemic and pulmonary channels in children with right isomerism. RESULTS:We studied 33 patients (17 females). Atrial situs was classified into solitus and inversus in 21 and 12 patients, respectively. Atrioventricular valve morphology included unilateral insertion in 15/33 (46%), balanced insertion into both ventricles in 11/33 (33%), unbalanced insertion into both ventricles in 7/33 (21%), and common atrioventricular valve in 27/33 (82%). The pulmonary connection included atresia and stenosis in 14/33 (42%) and 17/33 (52%), respectively. The anteroposterior relationship between the aorta and the pulmonary trunk was observed in 15/33 (46%). Total anomalous pulmonary venous connection concurred in 21/33 (63%), including supracardiac type in 16/21 (76%) and infracardiac type in 2/21 (10%). Preoperative pulmonary venous obstruction was found in 10/21 (47%). There were 14 patients with bilateral superior caval veins (42%). The anteroposterior relationship between the aorta and the pulmonary trunk was significantly correlated to the pulmonary arterial and venous channel anomalies (p = 0.001 and p = 0.027). CONCLUSIONS:The spatial relationship between the systemic and pulmonary channels was associated with distinct cardiovascular morphology associated with right isomerism.

In preterm infants with large ventricular septal defects (VSD), severe chronic lung disease (CLD), and pulmonary hypertension (PH), hemodynamic instability may occur after open-heart surgery. The selection of first pulmonary artery banding or one stage VSD closure is a clinical issue. At present, no guidelines exist to support decision-making in this unique population. This study reports the case of a preterm infant with a gestational age of 23 weeks and 4 days, a birth weight of 540 g, and elevated immunoglobulin-M levels, who was successfully treated with pulmonary artery banding and subsequently VSD closure. Before pulmonary artery banding, the pulmonary-to-systemic blood flow ratio was 2.5 and pulmonary vascular resistance was 2.6 U·m2 under general anesthesia with FiO2 = 0.6. However, pulmonary artery banding preceded considering the severe CLD and the risk of PH crisis after cardiopulmonary bypass. In a review of the literature on preterm infants with VSD with CLD and PH, only five infants, including the one in this case, were found. One infant underwent pulmonary artery banding first and survived, and three infants underwent one-stage VSD closure, after which one died (trisomy 21) due to a postoperative PH crisis. Three of the five cases underwent tracheostomy. The selection of first pulmonary artery banding or one-stage VSD closure needs to be carefully considered on a case-by-case basis, taking into consideration the severity of the VSD with CLD and PH. A future registry study will be needed to review these cases and clarify the outcome of the two strategies.

Background Management strategies of unplanned hospitalizations (UPH) vary and have not been well characterized in patients with Fontan circulation. Methods We prospectively followed 3226 Fontan patients for 3 years to characterize the current UPH status and elucidate the associations between in‐hospital management strategies and postdischarge outcomes. Results A total of 243 UPHs occurred (2.5 cases/100 person‐years). Fontan‐related UPHs accounted for 154 cases (63%), most commonly due to heart failure (19%), protein‐losing enteropathy (16%), hemorrhage (14%), arrhythmia (9%), thromboembolism (3%), and plastic bronchitis (2%). Fontan‐unrelated UPHs (89 cases; 37%) were mainly due to infections (19%). Adult patients were more frequently hospitalized for hemorrhage and thromboembolism (P<0.05). The longest length of hospital stay was observed in protein‐losing enteropathy, followed by thromboembolism and heart failure. Among nonpharmacological treatments, oxygen therapy was commonly used, followed by surgical procedures and catheter‐based interventions. Among pharmacological treatments, diuretics were commonly administered, followed by heparin and catecholamines. Of 240 patients discharged alive, 76 (15.4 cases/100 person‐years) were readmitted. Protein‐losing enteropathy was the most frequent cause of readmission, followed by heart failure and hemorrhage. In addition to conventional risk factors, in‐hospital management practices, such as oxygen therapy, surgical intervention, and diuretic adjustment were associated with readmission risk (P<0.01–0.001). Conclusions We clarified real‐world practices related to UPHs in Fontan patients. Specific in‐hospital treatment strategies were associated with the risk of readmission. Further studies are warranted to determine the causal relationships between treatment approaches and outcomes for standardized management strategies.

Background: Idiopathic/heritable pulmonary arterial hypertension (I/H-PAH), a disease with poor prognosis, often faces diagnostic delays due to nonspecific initial symptoms. In Japan, school ECG screening, performed in every 3 years for all students, identifies 41% of school-aged I/H-PAH patients; these typically show elevated pulmonary artery pressure (PAP) but have minimal symptoms (WHO-FC I/II) and preserved RV function. In this disease, the duration from the appearance of pulmonary vascular lesions to PH manifestation and the subsequent onset of RV failure are unknown. Objective: To address the precise pathological trajectory leading to PH manifestation, PH-related ECG findings at diagnosis (Dx) and pre-Dx in pediatric PAH patients were investigated utilizing Japan's school ECG screening system. Methods: Observational study of I/H-PAH patients (6-18 years), newly diagnosed 2005-2020, in Japanese pediatric cardiology teaching hospitals. School ECGs at/pre Dx were evaluated for PH-related findings (R≥1.5mV in V1, RV strain, Q in V1, IRBBB, inverted T waves) according to the criteria from the Japanese Society of Pediatric Cardiology and Cardiac Surgery. Results: In the survey, 118/143 institutions (82.5%) responded; 45 (38%) of those reported cases. 88 patients (51M, 37F; mean age 10.7y) were analyzed. Mode of detection of PAH were school ECG screening (n=36), symptoms (44), family history (5), and incidental findings (3). Compared to nonscreening group, the school screening group had higher proportion of WHO-FC I/II (91% vs 57%, p<.01) and lower plasma BNP (20 vs 102 pg/mL, p<.01), with comparable mean PAP (48 vs 55 mmHg, p=.65) and PVRI (12.1 vs 15.8 WU×m 2 , p=.38). PH-related ECG findings at Dx (n=87), which were present in 93% of all patients, were largely comparable between the groups (95% vs 91, p=.68), with the exception of higher prevalence of Q waves in V1 in the nonscreening (31% vs 15, p<.05) and R≥1.5mV in V1 in the screening group (59% vs 30, p<.05). Crucially, among 35 pre-Dx ECGs, PH-related abnormalities were observed in 77% (10/13) of those taken within 2 years of Dx, versus only 14% (3/22, p<.01) of those taken >2 years prior. Conclusion: Pre-Dx ECG analysis indicates PH-related findings can appear up to 2 years before symptom manifestation, suggesting a 1-2 year window of established PH with minimal symptoms in many pediatric patients. This highlights the potential for earlier diagnosis by performing ECG screening at even shorter intervals.

It is controversial whether children with isolated aortic valvular stenosis (vAS) initially undergo transcatheter or surgical aortic valvuloplasty (BAV or SAV). This multicenter retrospective case–control study aimed to explore outcomes after BAV or SAV for pediatric vAS. We studied children (aged < 15 years) with vAS treated at 4 tertiary congenital heart centers, and compared the rates of survival, reintervention, and valve replacement between patients with BAV and SAV. A total of 73 subjects (BAV: N = 52, SAV: N = 21) were studied. Age and aortic annulus z-score at the first presentation were 85 (26–530) days and − 0.45 (− 1.51–0.59), respectively. During the follow-up period of 121 (47–185) months, rates of 10-year survival (BAV: 88

Background Left ventricular noncompaction (LVNC) is a hereditary type of cardiomyopathy characterized by prominent trabeculations. Detailed characteristics of biventricular noncompaction (BiVNC) remain unknown. This study aimed to elucidate the clinical characteristics and genetic landscape of BiVNC. Methods and Results We recruited children with left ventricular noncompaction from Japanese multi‐institutional centers from 2013 to 2021. Left ventricular noncompaction was classified as BiVNC, congenital heart disease, arrhythmia, dilated cardiomyopathy, or normal function. In these patients, cardiomyopathy‐associated genes were screened. A total of 234 patients (127 male; mean age, 4 months [range, 0–6.6 years]) were enrolled in this study, of whom 25 had BiVNC; 55, normal function; 84, dilated cardiomyopathy; 38, congenital heart disease; and 32, arrhythmia. BiVNC was diagnosed during the perinatal period in 10 patients, in whom the prevalence was higher than that in other patients. A total of 14 patients in the group with BiVNC had congenital heart disease, but not necessarily right heart lesions. Left ventricular dyskinesis was frequently observed in the lateral wall (24%) and apex (28%). Eleven pathogenic variants were found in 11 patients with BiVNC (44.0%). The group with BiVNC had a higher ratio of mitochondrial and developmental gene variants than the other groups. Among all groups, the group with BiVNC had the worst survival rate ( P =0.0009). Conclusions Pediatric patients with BiVNC had a high rate of ventricular dyskinesis and poor outcome. A comprehensive and careful screening for disease‐causing genes and phenotype may help identify specific patients with left ventricular noncompaction and mortality‐related cardiac phenotypes.

Abstract Background A left thoracotomy approach is anatomically appropriate for childhood aortic coarctation; however, the pediatric femoral arteriovenous diameters are too small for cardiopulmonary bypass cannulation. We aimed to determine the safety of a partial cardiopulmonary bypass through the main pulmonary artery and the descending aorta in pediatric aortic coarctation repair. Methods We retrospectively reviewed 10 patients who underwent coarctation repair under partial main pulmonary artery-to-descending aorta cardiopulmonary bypass with a left thoracotomy as the CPB group. During the same period, 16 cases of simple coarctation of the aorta repair, with end-to-end anastomosis through a left thoracotomy without partial CPB assistance, were included as the non-CPB group to evaluate the impact of partial CPB. Results The median age and weight at surgery of the CPB group were 3.1 years (range, 9 days to 17.9 years) and 14.0 (range, 2.8–40.7) kg, respectively. Indications for the partial cardiopulmonary bypass with overlap were as follows: age > 1 year (n = 7), mild aortic coarctation (n = 3), and predicted ischemic time > 30 min (n = 5). Coarctation repair using autologous tissue was performed in seven cases and graft replacement in three. The mean partial cardiopulmonary bypass time, descending aortic clamp time, and cardiopulmonary bypass flow rate were 73 ± 37 min, 57 ± 27 min, and 1.6 ± 0.2 L/min/m2, respectively. Urine output during descending aortic clamping was observed in most cases in the CPB group (mean: 9.1 ± 7.9 mL/kg/h), and the total intraoperative urine output was 3.2 ± 2.7 mL/kg/h and 1.2 ± 1.5 mL/kg/h in the CPB and non-CPB group, respectively (p = 0.020). The median ventilation time was 1 day (range, 0–15), and the intensive care unit stay duration was 4 days (range, 1–16) with no surgical deaths. No major complications, including paraplegia or recurrent coarctation, occurred postoperatively during a median observation period of 8.1 (range, 3.4–17.5) years in the CPB group. In contrast, reoperation with recurrent coarctation was observed in 2 cases in the non-CPB group (p = 0.37). Conclusions Partial cardiopulmonary bypass through the main pulmonary artery and descending aorta via a left thoracotomy is a safe and useful option for aortic coarctation repair in children.

Background: Dilated cardiomyopathy (DCM) is a progressive myocardial disorder characterized by impaired cardiac contraction and ventricular dilation. However, some patients with DCM improve when experiencing left ventricular reverse remodeling (LVRR). Currently, the detailed association between genotypes and clinical outcomes, including LVRR, particularly among children, remains uncertain. Methods: Pediatric patients with DCM from multiple Japanese institutions recorded between 2014 and 2023 were enrolled. We identified their DCM-related genes and explored the association between gene variants and clinical outcomes, including LVRR. Results: We included 123 pediatric patients (62 males; median age: 8 [1–51] months) and found 50 pathogenic variants in 45 (35.0%) of them. The most identified gene was MYH7(14.0%), followed by RYR2 (12.0%) and TPM1 (8.0%). LVRR was achieved in 47.5% of these patients. The left ventricular ejection fraction remained unchanged (31.4% to 39.8%, P = 0.1913) in patients with sarcomere gene variants but significantly increased in those with nonsarcomere gene variants (33.4% to 47.8%, P = 0.0466) and those without gene variants (33.6% to 54.1%, P = 0.003). Conclusions: LVRR was not uniform across functional gene groups. Hence, an individualized gene-guided prediction approach may be adopted for children with DCM.

Although the molecular mechanisms underlying congenital heart disease (CHD) remain poorly understood, recent advances in genetic analysis have facilitated the exploration of causative genes for CHD. We reported that the pathogenic variant c.1617del of TMEM260 , which encodes a transmembrane protein, is highly associated with CHD, specifically persistent truncus arteriosus (PTA), the most severe cardiac outflow tract (OFT) defect. Using whole-exome sequencing, the c.1617del variant was identified in two siblings with PTA in a Japanese family and in three of the 26 DNAs obtained from Japanese individuals with PTA. The c.1617del of TMEM260 has been found only in East Asians, especially Japanese and Korean populations, and the frequency of this variant in PTA is estimated to be next to that of the 22q11.2 deletion, the most well-known genetic cause of PTA. Phenotype of patients with c.1617del appears to be predominantly in the heart, although TMEM260 is responsible for structural heart defects and renal anomalies syndrome (SHDRA). The mouse TMEM260 variant (p.W535Cfs*56), synonymous with the human variant (p.W539Cfs*9), exhibited truncation and downregulation by western blotting, and aggregation by immunocytochemistry. In situ hybridization demonstrated that Tmem260 is expressed ubiquitously during embryogenesis, including in the development of cardiac OFT implicated in PTA. This expression may be regulated by a ~ 0.8 kb genomic region in intron 3 of Tmem260 that includes multiple highly conserved binding sites for essential cardiac transcription factors, thus revealing that the c.1617del variant of TMEM260 is the major single-gene variant responsible for PTA in the Japanese population.

BACKGROUND:Peripheral pulmonary stenosis (PPS) is a condition characterized by the narrowing of the pulmonary arteries, which impairs blood flow to the lung. The mechanisms underlying PPS pathogenesis remain unclear. Thus, the aim of this study was to investigate the genetic background of patients with severe PPS to elucidate the pathogenesis of this condition. METHODS AND RESULTS:We performed genetic testing and functional analyses on a pediatric patient with PPS and Williams syndrome (WS), followed by genetic testing on 12 patients with WS and mild-to-severe PPS, 50 patients with WS but not PPS, and 21 patients with severe PPS but not WS. Whole-exome sequencing identified a rare PTGIS nonsense variant (p.E314X) in a patient with WS and severe PPS. Prostaglandin I2 synthase (PTGIS) expression was significantly downregulated and cell proliferation and migration rates were significantly increased in cells transfected with the PTGIS p.E314X variant-encoding construct when compared with that in cells transfected with the wild-type PTGIS-encoding construct. p.E314X reduced the tube formation ability in human pulmonary artery endothelial cells and caspase 3/7 activity in both human pulmonary artery endothelial cells and human pulmonary artery smooth muscle cells. Compared with healthy controls, patients with PPS exhibited downregulated pulmonary artery endothelial prostaglandin I2 synthase levels and urinary prostaglandin I metabolite levels. We identified another PTGIS rare splice-site variant (c.1358+2T>C) in another pediatric patient with WS and severe PPS. CONCLUSIONS:In total, 2 rare nonsense/splice-site PTGIS variants were identified in 2 pediatric patients with WS and severe PPS. PTGIS variants may be involved in PPS pathogenesis, and PTGIS represents an effective therapeutic target.

For adults, the standard procedure for mitral valve repair of Carpentier classification type II mitral regurgitation is reconstruction with artificial chordae. In children, placement of artificial chordae of precise length between the papillary muscle and prolapsed mitral leaflet in the restricted mitral subvalvular space is technically difficult. We successfully performed mitral valve repair in 3 pediatric patients using a modified fixed loop-in-loop technique.

OBJECTIVE:This study aimed to explore anatomical and hemodynamic features of atrial septal defect, which was treated by transcatheter device closure late after completion of biventricular circulation in patients with pulmonary atresia and intact ventricular septum (PAIVS) or critical pulmonary stenosis (CPS).METHODS:We studied echocardiographic and cardiac catheterization data, including defect size, retroaortic rim length, single or multiple defects, the presence of malalignment atrial septum, tricuspid and pulmonary valve diameters, and cardiac chamber sizes, in patients with PAIVS/CPS who underwent transcatheter closure of atrial septal defect (TCASD), and compared to control subjects.RESULTS:A total of 173 patients with atrial septal defect, including 8 patients with PAIVS/CPS, underwent TCASD. Age and weight at TCASD were 17.3 ± 18.3 years and 36.6 ± 13.9 kg, respectively. There was no significant difference in defect size (13.7 ± 4.0 vs. 15.6 ± 5.2 mm, p = 0.317) and the retro-aortic rim length (3.7 ± 4.3 vs. 3.6 ± 0.3.1 mm, p = 0.948) between the groups; however, multiple defects (50% vs. 5%, p < 0.001) and malalignment atrial septum (62% vs. 14%. p < 0.001) were significantly frequent in patients with PAIVS/CPS compared to control subjects. The ratio of pulmonary to systemic blood flow in patients with PAIVS/CPS was significantly lower than that in the control patients (1.2 ± 0.4 vs. 2.0 ± 0.7, p < 0.001); however, four out of eight patients with atrial septal defect associated with PAIVS/CPS had right-to-left shunt through a defect, who were evaluated by the balloon occlusion test before TCASD. The indexed right atrial and ventricular areas, the right ventricular systolic pressure, and mean pulmonary arterial pressure did not differ between the groups. After TCASD, the right ventricular end-diastolic area remained unchanged in patients with PAIVS/CPS, whereas it significantly decreased in control subjects.CONCLUSIONS:Atrial septal defect associated with PAIVS/CPS had more complex anatomy, which would be a risk for device closure. Hemodynamics should be individually evaluated to determine the indication for TCASD because PAIVS/CPS encompassed anatomical heterogeneity of the entire right heart.

BACKGROUND:Cardiac calmodulinopathy, characterized by a life-threatening arrhythmia and sudden death in the young, is extremely rare and caused by genes encoding calmodulin, namely calmodulin 1 (CALM1), CALM2, and CALM3. METHODS AND RESULTS:We screened 195 symptomatic children (age 0-12 years) who were suspected of inherited arrhythmias for 48 candidate genes, using a next-generation sequencer. Ten probands were identified as carrying variants in any of CALM1-3 (5%; median age 5 years), who were initially diagnosed with long QT syndrome (LQTS; n=5), catecholaminergic polymorphic ventricular tachycardia (CPVT; n=3), and overlap syndrome (n=2). Two probands harbored a CALM1 variant and 8 probands harbored 6 CALM2 variants. There were 4 clinical phenotypes: (1) documented lethal arrhythmic events (LAEs): 4 carriers of N98S in CALM1 or CALM2; (2) suspected LAEs: CALM2 p.D96G and D132G carriers experienced syncope and transient cardiopulmonary arrest under emotional stimulation; (3) critical cardiac complication: CALM2 p.D96V and p.E141K carriers showed severe cardiac dysfunction with QTc prolongation; and (4) neurological and developmental disorders: 2 carriers of CALM2 p.E46K showed cardiac phenotypes of CPVT. Beta-blocker therapy was effective in all cases except cardiac dysfunction, especially in combination with flecainide (CPVT-like phenotype) and mexiletine (LQTS-like). CONCLUSIONS:Calmodulinopathy patients presented severe cardiac features, and their onset of LAEs was earlier in life, requiring diagnosis and treatment at the earliest age possible.