Decreased smooth muscle cells and fibrous thickening of the tunica media in peripheral pulmonary artery stenosis in Alagille syndrome.

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.

Monitoring Berlin Heart EXCOR by computer vision: A preliminary implementation and evaluation.

BACKGROUND: EXCOR Pediatric is one of the most commonly used ventricular assist devices (VAD) for small children; it requires visual inspection of the diaphragm movement to assess its operating status. Although this visual inspection can only be performed by trained medical professionals, it can also be attempted by the recent advances in computer vision technology. METHODS: Movement of the diaphragm in the operating EXCOR VAD was recorded as movies and annotated frame-by-frame in three classes according to the state of the diaphragm: "fill," "mid," and "empty." Three models, MobileNetV3, EfficientNetV2, and MobileViT, were trained using the frames, and their performance was evaluated based on the accuracy and area under the receiver operating characteristic curve (AROC). RESULTS: A total of 152 movies were available from two participants. Only the 10 mL pumps were used. Ninety-eight movies were used for annotation and frame extraction, and 7949 frames per class were included in the analysis. The macro-average accuracies of the three models were 0.88, 0.91, and 0.93, and the AROC were 0.99, 0.98, and 0.99 for MobileNetV3, EfficientNetV2, and MobileViT, respectively. CONCLUSION: Image recognition models based on lightweight deep neural networks could detect the diaphragm state of EXCOR VAD with sufficient accuracy, although there were limited variations in the dataset. This suggests the potential of computer vision for the automated monitoring of the EXCOR diaphragm position.

A leadless pacemaker implantation for a patient with systemic right ventricle under ventricular assist device support.

Patients with congenitally corrected transposition of the great arteries (ccTGA) often develop complete atrioventricular block and heart failure due to the abnormal disposition of atrioventricular node and disadvantage of systemic right ventricle. These issues are managed with a pacing system and a ventricular assist device (VAD), respectively. While technological advances offer new treatment strategies, the simultaneous deployment of a leadless pacemaker and a VAD in cases of ccTGA remains unexplored. Here, we present a case of leadless pacemaker implantation for a VAD-supported ccTGA patient. The safety of a leadless pacemaker for a subpulmonary left ventricle and electromagnetic interference between devices are major concerns when implanting a leadless pacemaker; however, the current case overcomes these obstacles. There were no perioperative complications, and both devices were functioning without problems during a one-year follow up. We expect that, even in patients with cardiac complexity such as systemic right ventricle under VAD support, a leadless pacemaker could become the treatment of choice if the indication is appropriate, although careful and close follow up is needed. Learning objective: Technological advances expand treatment strategies and provide significant benefits to patients with adult congenital heart disease (ACHD). However, discussion of the combination of a leadless pacemaker and a ventricular assist device (VAD) is rare. We demonstrated the efficacy of a leadless pacemaker for a subpulmonary left ventricle in a patient with systemic right ventricle on VAD. This approach could be an option even for ACHD patients.

Prediction of adverse cardiovascular events in children using artificial intelligence-based electrocardiogram.

BACKGROUND: Convolutional neural networks (CNNs) have emerged as a novel method for evaluating heart failure (HF) in adult electrocardiograms (ECGs). However, such CNNs are not applicable to pediatric HF, where abnormal anatomy of congenital heart defects plays an important role. ECG-based CNNs reflecting neurohormonal activation (NHA) may be a useful marker of pediatric HF. This study aimed to develop and validate an ECG-derived marker of pediatric HF that reflects the risk of future cardiovascular events. METHODS: Based on 21,378 ECGs from 8324 children, a CNN was trained using B-type natriuretic peptide (BNP) and the occurrence of major adverse cardiovascular events (MACEs). The output of the model, or the electrical heart failure indicator (EHFI), was compared with the BNP regarding its ability to predict MACEs in 813 ECGs from 295 children. RESULTS: EHFI achieved a better area under the curve than BNP in predicting MACEs within 180 days (0.826 versus 0.691, p = 0.03). On Cox univariable analyses, both EHFI and BNP were significantly associated with MACE (log10 EHFI: hazard ratio [HR] = 16.5, p < 0.005 and log10 BNP: HR = 4.4, p < 0.005). The time-dependent average precisions of EHFI in predicting MACEs were 32.4%-67.9% and 1.6-7.5-fold higher than those of BNP in the early period. Additionally, the MACE rate increased monotonically with EHFI, whereas the rate peaked at approximately 100 pg/mL of BNP and decreased in the higher range. CONCLUSIONS: ECG-derived CNN is a novel marker of HF with different prognostic potential from BNP. CNN-based ECG analysis may provide a new guide for assessing pediatric HF.

Removal of central venous catheter using Evolution® Rotating Dilator.

We experienced the first case of a difficult-to-extract central venous catheter removed with a pacemaker lead removal system: a 14-year-old boy with Hirschsprung's disease who had repeated catheter infections that could not be removed by traction. Because the catheter lumen was occluded, a suture was tied around the end of the catheter and the catheter was removed with a rotating dilator.

Hemodynamic simulation of complete transposition of the great arteries for optimal treatment strategies based on its circulatory physiology.

Our study aimed to elucidate the role of different shunts and provide novel insights into optimal treatment approaches for complete transposition of the great arteries (TGA), which is characterized by unique and complicated circulatory dynamics. We constructed a computational cardiovascular TGA model and manipulated cardiovascular parameters, such as atrial septal defect (ASD) and patent ductus arteriosus (PDA) sizes, to quantify their effects on oxygenation and hemodynamics. In addition, ASD flow patterns were investigated as innovative indications for balloon atrial septostomy (BAS). Our model of TGA with an intact ventricular septum (TGA-IVS) showed that a large ASD can achieve sufficient mixing for survival without PDA, and the presence of PDA is detrimental to oxygen delivery. A treatment strategy for TGA-IVS that enlarges the ASD as much as possible by BAS and PDA closure would be desirable. In TGA with a ventricular septal defect (TGA-VSD), the VSD allows for higher oxygenation and reduces the detrimental effects of PDA on systemic circulation. In TGA-VSD, both strategies of enlarging the ASD by BAS with a closed PDA and adjusting the PDA in response to pulmonary vascular resistance (PVR) reduction without BAS may be effective. The simulated ASD flow patterns showed that the sharp peak left-to-right flow pattern in systole (σ-wave) reflected the hemodynamically significant ASD size, independent of PDA, VSD, and PVR. The ASD flow pattern visualized by Doppler echocardiography provides clinical insights into the significance of an ASD and indications for BAS, which are not readily apparent through morphological assessment.NEW & NOTEWORTHY Complete transposition of the great arteries (TGA) represents complex and unique circulation that is dependent on blood mixing through multiple interacting shunts. Consequently, the role of each shunt and the treatment strategy remain unclear. We developed a mathematical model of TGA circulation, revealing the significant influence of atrial septal defect (ASD) on oxygenation and hemodynamics. The blood flow pattern through the ASD reflects its hemodynamic impact and helps determine treatment strategies.

A novel pathogenic variant located just upstream of the C-terminal Ser423-X-Ser425 phosphorylation motif in SMAD3 causing Loeys-Dietz syndrome.

OBJECTIVE: Loeys-Dietz syndrome (LDS) is a heritable disorder of connective tissue closely related to Marfan syndrome (MFS). LDS is caused by loss-of-function variants of genes that encode components of transforming growth factor-ß (TGF-ß) signaling; nevertheless, LDS type 1/2 caused by TGFBR1/2 pathogenic variants is frequently found to have paradoxical increases in TGF-ß signaling in the aneurysmal aortic wall. Here, we present a Japanese LDS family having a novel SMAD3 variant. METHODS: The proband was tested via clinical, genetic, and histological analyses. In vitro analysis was performed for pathogenic evaluation. RESULTS: The novel heterozygous missense variant of SMAD3 [c.1262G>A, p.(Cys421Tyr)], located just upstream of the C-terminal Ser423-X-Ser425 phosphorylation motif, was found in this instance of LDS type 3. This variant led to reduced phospho-SMAD3 (Ser423/Ser425) levels and transcription activity in vitro; however, a paradoxical upregulation of TGF-ß signaling was evident in the aortic wall. CONCLUSIONS: Our results revealed the presence of TGF-ß paradox in this case with the novel loss-of-function SMAD3 variant. The precise mechanism underlying the paradox is unknown, but further research is warranted to clarify the influence of the SMAD3 variant type and location on the LDS3 phenotype as well as the molecular mechanism leading to LDS3 aortopathy.

Reduced volume and altered composition of paraspinal muscles in Marfan syndrome: A retrospective cohort study.

Retrospective cohort study. Spinal deformities in patients with Marfan syndrome (MFS) are distinct from those in patients with idiopathic scoliosis (IS). It is more prone to progression and more likely to present with sagittal malalignment than IS. However, the etiology of this characteristic spinal deformity in MFS remains unclear. This study aimed to determine the spinal musculature characteristics in patients with MFS on the hypothesis that the paraspinal muscles of patients with MFS would be qualitatively or quantitatively different from those of patients with IS. Seventeen consecutive patients with MFS aged 25 years or younger undergoing surgery for scoliosis in our hospital were compared with age- and sex-matched patients with IS undergoing surgery for scoliosis. The body size-adjusted relative cross-sectional area (rCSA), fatty infiltration ratio (FI%), and relative functional cross-sectional area (rFCSA) of the psoas muscles (PM) and paravertebral muscles (PVM) at L3/4 and L4/5 were measured using preoperative T2-weighted magnetic resonance imaging. Functional CSA was defined as total CSA minus the fatty infiltration area of each muscle and rFCSA was calculated as the body size-adjusted functional CSA. The rCSA of the PM at L3/4 and L4/5 was significantly smaller in the MFS group than in the IS group (L3/4, P = .021; L4/5, P = .002). The FI% of the PM at L4/5 was significantly higher in the MFS group (P = .044). Consequently, the rFCSA of the PM at L3/4 and L4/5 and the rFCSA of the PVM at L3/4 in the MFS group were significantly smaller than those in the IS group (PM at L3/4, P = .021; PM at L4/5, P = .001; PVM at L3/4, P = .025). Compared with patients with IS, patients with MFS exhibited significantly decreased body-size-adjusted CSA of the PM and reduced body-size-adjusted functional CSA of the PVM and PM. These findings may partially explain the characteristics of distinctive spinal deformities in patients with MFS.

Association Between Maternal Factors in Early Pregnancy and Congenital Heart Defects in Offspring: The Japan Environment and Children's Study.

Background Many prenatal factors are reported to be associated with congenital heart defects (CHD) in offspring. However, these associations have not been adequately examined using large-scale birth cohorts. Methods and Results We evaluated a data set of the Japan Environmental and Children's Study. The primary outcome was a diagnosis of CHD by age 2 years. We defined the following variables as exposures: maternal baseline characteristics, fertilization treatment, maternal history of diseases, socioeconomic status, maternal alcohol intake, smoking, tea consumption, maternal dietary intake, and maternal medications and supplements up to 12 weeks of gestation. We used multivariable logistic regression analysis to assess the associations between various exposures and CHD in offspring. A total of 91 664 singletons were included, among which 1264 (1.38%) had CHD. In multivariable analysis, vitamin A supplements (adjusted odds ratio [aOR], 5.78 [95% CI, 2.30-14.51]), maternal use of valproic acid (aOR, 4.86 [95% CI, 1.51-15.64]), maternal use of antihypertensive agents (aOR, 3.80 [95% CI, 1.74-8.29]), maternal age ≥40 years (aOR, 1.59 [95% CI, 1.14-2.20]), and high maternal hemoglobin concentration in the second trimester (aOR, 1.10 per g/dL [95% CI, 1.03-1.17]) were associated with CHD in offspring. Conclusions Using a Japanese large-scale birth cohort study, we found 6 maternal factors to be associated with CHD in offspring.

Factors affecting in-hospital mortality among pediatric patients with myocarditis treated with mechanical circulatory support.

BACKGROUND: Mechanical circulatory support (MCS) is a common treatment modality for circulatory failure caused by pediatric myocarditis. Despite improvements in treatment strategy, the mortality rate of pediatric patients with myocarditis treated with MCS is still high. Identifying the factors associated with mortality among pediatric patients with myocarditis treated with MCS may help reduce the mortality rate. METHODS: This retrospective cohort study examined the data of patients aged <16 years who were admitted to a hospital between July 2010 and March 2018 for myocarditis; the data were collected from the Diagnosis Procedure Combination database, which is a national inpatient database in Japan. RESULTS: During the study period, 105 of the 598 patients with myocarditis were treated with MCS. We excluded seven patients who died within 24 h of admission, resulting in 98 eligible patients. The overall in-hospital mortality was 22 %. In-hospital mortality was higher among patients aged <2 years and those who received cardiopulmonary resuscitation (CPR). Multivariable logistic regression analysis showed significantly higher in-hospital mortality among patients aged <2 years old [odds ratio (OR), 6.57; 95 % confidence interval (CI), 1.89-22.87] and those who received CPR (OR, 4.70; 95 % CI, 1.51-14.63; p < 0.01). CONCLUSION: The in-hospital mortality of pediatric patients with myocarditis treated with MCS was high, particularly of children younger than 2 years and those who received CPR.

Cardiovascular Complications of Down Syndrome: Scoping Review and Expert Consensus.

Cardiovascular disease is a leading cause of morbidity and mortality in individuals with Down syndrome. Congenital heart disease is the most common cardiovascular condition in this group, present in up to 50% of people with Down syndrome and contributing to poor outcomes. Additional factors contributing to cardiovascular outcomes include pulmonary hypertension; coexistent pulmonary, endocrine, and metabolic diseases; and risk factors for atherosclerotic disease. Moreover, disparities in the cardiovascular care of people with Down syndrome compared with the general population, which vary across different geographies and health care systems, further contribute to cardiovascular mortality; this issue is often overlooked by the wider medical community. This review focuses on the diagnosis, prevalence, and management of cardiovascular disease encountered in people with Down syndrome and summarizes available evidence in 10 key areas relating to Down syndrome and cardiac disease, from prenatal diagnosis to disparities in care in areas of differing resource availability. All specialists and nonspecialist clinicians providing care for people with Down syndrome should be aware of best clinical practice in all aspects of care of this distinct population.

Effect of procedural volume on the outcomes of congenital heart surgery in Japan.

OBJECTIVES: The present study developed a new risk model for congenital heart surgery in Japan and determined the relationship between hospital procedural volume and mortality using the developed model. METHODS: We analyzed 47,164 operations performed between 2013 and 2018 registered in the Japan Cardiovascular Surgery Database-Congenital and created a new risk model to predict the 90-day/in-hospital mortality using the Japanese congenital heart surgery mortality categories and patient characteristics. The observed/expected ratios of mortality were compared among 4 groups based on annual hospital procedural volume (group A [5539 procedures performed in 90 hospitals]: ≤50, group B [9322 procedures in 24 hospitals]: 51-100, group C [13,331 procedures in 21 hospitals]: 101-150, group D [18,972 procedures in 15 hospitals]: ≥151). RESULTS: The overall mortality rate was 2.64%. The new risk model using the surgical mortality category, age-weight categories, urgency, and preoperative mechanical ventilation and inotropic use achieved a c-index of 0.81. The observed/expected ratios based on the new risk model were 1.37 (95% confidence interval, 1.18-1.58), 1.21 (1.08-1.33), 1.04 (0.94-1.14), and 0.78 (0.71-0.86) in groups A, B, C, and D, respectively. In the per-procedure analysis, the observed/expected ratios of the Rastelli, coarctation complex repair, and arterial switch procedures in group A were all more than 3.0. CONCLUSIONS: The risk-adjusted mortality rate for low-volume hospitals was high for not only high-risk but also medium-risk procedures. Although the overall mortality rate for congenital heart surgeries is low in Japan, the observed volume-mortality relationship suggests potential for improvement in surgical outcomes.

Predictors of liver cirrhosis and hepatocellular carcinoma among perioperative survivors of the Fontan operation.

OBJECTIVE: Fontan-associated liver disease (FALD) is widely recognised as a common complication in patients long after the Fontan operation. However, data on the predictors of FALD that can guide its screening and management are lacking. The present study aimed to identify the predictors of liver cirrhosis (LC) and hepatocellular carcinoma (HCC) in post-Fontan patients. METHODS: This was a multi-institutional retrospective cohort study. Clinical data of all perioperative survivors of Fontan operation before 2011 who underwent postoperative catheterisation were collected through a retrospective chart review. RESULTS: A total of 1117 patients (538 women, 48.2%) underwent their first Fontan operation at a median age of 3.4 years. Postoperative cardiac catheterisation was conducted at a median of 1.0 year. During a median follow-up period of 10.3 years, 67 patients (6.0%) died; 181 (16.2%) were diagnosed with liver fibrosis, 67 (6.0%) with LC, 54 (4.8%) with focal nodular hyperplasia and 7 (0.6%) with HCC. On multivariable analysis, high central venous pressure (CVP) (HR, 1.28 (95% CI 1.01 to 1.63) per 3 mm Hg; p=0.042) and severe atrioventricular valve regurgitation (HR, 6.02 (95% CI 1.53 to 23.77); p=0.010) at the postoperative catheterisation were identified as independent predictors of LC/HCC. CONCLUSIONS: Patients with high CVP and/or severe atrioventricular valve regurgitation approximately 1 year after the Fontan operation are at increased risk of developing advanced liver disease in the long term. Whether therapeutic interventions to reduce CVP and atrioventricular valve regurgitation decrease the incidence of advanced liver disease requires further elucidation.

Successful transesophageal pacing in a very-low-birth-weight-infant with atrioventricular block.

A baby with complete atrioventricular block was born with a birth weight of 1403 g. Isoproterenol was ineffective and emergency pacing was required. Since transcutaneous pacing was ineffective and transvenous pacing was untenable due to small body size, transesophageal pacing was performed for 3.5 hours until permanent pacemaker implantation. There were no complications. This is the first report of continuous transesophageal pacing in a very-low-birth-weight infant.

Successful use of ivabradine in a 10-year-old patient with graft failure after heart transplantation.

We encountered a paediatric case of graft failure due to antibody-mediated rejection after heart transplantation in which ivabradine was effective. Inappropriate sinus tachycardia in denervated transplanted hearts is a good indication for ivabradine administration as beta-blockers have a limited efficacy. To our knowledge, this is the first report on the effectiveness of ivabradine in a paediatric heart transplant rejection case.

Impact of pathogenic FBN1 variant types on the development of severe scoliosis in patients with Marfan syndrome.

BACKGROUND: Among the several musculoskeletal manifestations in patients with Marfan syndrome, spinal deformity causes pain and respiratory impairment and is a great hindrance to patients' daily activities. The present study elucidates the genetic risk factors for the development of severe scoliosis in patients with Marfan syndrome. METHODS: We retrospectively evaluated 278 patients with pathogenic or likely pathogenic FBN1 variants. The patients were divided into those with (n=57) or without (n=221) severe scoliosis. Severe scoliosis was defined as (1) patients undergoing surgery before 50 years of age or (2) patients with a Cobb angle exceeding 50° before 50 years of age. The variants were classified as protein-truncating variants (PTVs), which included variants creating premature termination codons and inframe exon-skipping, or non-PTVs, based on their location and predicted amino acid alterations, and the effect of the FBN1 genotype on the development of severe scoliosis was examined. The impact of location of FBN1 variants on the development of severe scoliosis was also investigated. RESULTS: Univariate and multivariate analyses revealed that female sex, PTVs of FBN1 and variants in the neonatal region (exons 25-33) were all independent significant predictive factors for the development of severe scoliosis. Furthermore, these factors were identified as predictors of progression of existing scoliosis into severe state. CONCLUSIONS: We elucidated the genetic risk factors for the development of severe scoliosis in patients with Marfan syndrome. Patients harbouring pathogenic FBN1 variants with these genetic risk factors should be monitored carefully for scoliosis progression.

Practice and Safety of Static Balloon Atrial Septostomy Based on a Nationwide Registry Data.

BACKGROUND: Balloon atrial septostomy (BAS) is an essential catheterization procedure for congenital heart lesions. Recently, a balloon catheter for static BAS was approved for the first time in Japan as an alternative to the conventional pull-through BAS. Despite the expected increase in the use of static BAS, reports on its safety are scarce worldwide.Methods and Results: Data on static and pull-through BAS registered in a national registry between 2016 and 2018 were collected. During the study period, 247 sessions of static BAS and 588 sessions of pull-through BAS were performed on a total of 674 patients. Patients who underwent static BAS were older (P<0.001). The incidence of serious adverse events (4.3% vs. 0.9%, P=0.03) and the overall incidence of adverse events (8.1% vs. 3.2%, P=0.03) were higher in static BAS than in pull-through BAS. Among patients who underwent static BAS, the risk factor for adverse events was a body weight <3 kg at the time of the procedure (odds ratio: 4.3 [confidence interval: 1.7-11], P=0.003). CONCLUSIONS: This nationwide study revealed differences in patient background between static and pull-through BAS, as well as a higher incidence of adverse events related to static BAS. Patients weighing <3 kg are at high risk for adverse events after static BAS and may require surgical and circulatory support backup.