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Angiopoietin-2 is associated with chronic inflammation and angiogenesis, but its activity after Fontan operation in pediatric patients remains uncertain. We compared serum angiopoietin-2 levels in pediatric patients after Fontan operation versus those with congenital heart disease as a control group. A total of 185 patients (median age 7 [3 to 12] years, 106 males) were included, consisting of 140 in the Fontan group and 45 in the control group. Serum angiopoietin-2 levels were significantly higher in the Fontan group (7,670 vs 2,351 pg/ml, p <0.001). In the Fontan group, a serum angiopoietin-2 level ≥3.9 of common logarithm was an independent risk factor for death or Fontan-related adverse events with an adjusted hazard ratio of 6.25 (95% confidence interval 1.64 to 23.9, p = 0.007). In preoperative variables, desaturation was independently associated with increased serum angiopoietin-2 levels after Fontan operation (p = 0.047). In conclusion, serum angiopoietin-2 levels were elevated in the pediatric phase after Fontan operation. In Fontan patients, a higher serum angiopoietin-2 level was an independent risk factor for death or Fontan-related adverse events. The clinical implication of measuring and monitoring serum angiopoietin-2 levels in this cohort requires further investigation.

BackgroundKawasaki disease (KD) is a systemic vasculitis that is currently the most common cause of acquired heart disease in children. However, its etiology remains unknown. Long non-coding RNAs (lncRNAs) contribute to the pathophysiology of various diseases. Few studies have reported the role of lncRNAs in KD inflammation; thus, we investigated the role of lncRNA in KD inflammation.MethodsA total of 50 patients with KD (median age, 19 months; 29 males and 21 females) were enrolled. We conducted cap analysis gene expression sequencing to determine differentially expressed genes in monocytes of the peripheral blood of the subjects.ResultsAbout 21 candidate lncRNA transcripts were identified. The analyses of transcriptome and gene ontology revealed that the immune system was involved in KD. Among these genes, G0/G1 switch gene 2 (G0S2) and its antisense lncRNA, HSD11B1-AS1, were upregulated during the acute phase of KD (P < 0.0001 and <0.0001, respectively). Moreover, G0S2 increased when lipopolysaccharides induced inflammation in THP-1 monocytes, and silencing of G0S2 suppressed the expression of HSD11B1-AS1 and tumor necrosis factor-α.ConclusionsThis study uncovered the crucial role of lncRNAs in innate immunity in acute KD. LncRNA may be a novel target for the diagnosis of KD.ImpactThis study revealed the whole aspect of the gene expression profile of monocytes of patients with Kawasaki disease (KD) using cap analysis gene expression sequencing and identified KD-specific molecules: G0/G1 switch gene 2 (G0S2) and long non-coding RNA (lncRNA) HSD11B1-AS1.We demonstrated that G0S2 and its antisense HSD11B1-AS1 were associated with inflammation of innate immunity in KD.lncRNA may be a novel key target for the diagnosis of patients with KD.

Left ventricular noncompaction (LVNC) is a form of cardiomyopathy characterized by excessive trabeculation and a thin compacted myocardial layer. Variants in MYH7 , which encodes the β-myosin heavy chain, are among the most commonly identified genetic causes of LVNC. Despite its clinical relevance, the metabolic disturbances associated with LVNC remain poorly understood, and the pathophysiological mechanisms have not been investigated in an animal model of MYH7 -related LVNC. To address this gap, we generated a mouse model carrying the human MYH7 Gln315Arg (Q315R) variant, a representative mutation linked to LVNC. Mice with the MYH7 Q315R variant exhibited key features of LVNC, including impaired diastolic function, reduced contractility, and excessive trabeculations extending across the ventricular walls. Metabolomic analysis revealed significant metabolic remodeling, characterized by suppressed glycolysis, lipid oxidation, and tricarboxylic acid (TCA) cycle activity. Levels of key intermediates, including glucose-6-phosphate, pyruvate, and acetyl-CoA, were reduced, along with downregulated expression of glycolytic and mitochondrial genes. Additionally, alterations in the pentose phosphate pathway indicated impaired nucleic acid synthesis, while an increased lactate-to-pyruvate ratio suggested a metabolic shift toward anaerobic glycolysis. This study underscores the critical role of metabolic inflexibility—marked by suppression of glycolysis, lipid metabolism, and TCA cycle activity—in the pathophysiology of LVNC. Targeting these dysregulated metabolic pathways, particularly by enhancing mitochondrial function and restoring metabolic adaptability, presents a potential therapeutic strategy for LVNC treatment.

Kawasaki Disease (KD) is an acute inflammatory disease that takes the form of systemic vasculitis. Endothelial microparticles (EMPs) have been recognized as an important transcellular delivery system. We hypothesized whether EMPs are involved in vasculitis in acute KD. Fifty patients with acute KD were enrolled, divided into two subgroups: those with coronary artery lesions (CAL) (n = 5) and those without CAL (NCAL) (n = 45). EMPs were measured using flow cytometry, and microRNA (miR) expression profiling was performed by microRNA array. The percentage of EMPs in acute KD was significantly higher than in controls ( P  < 0.0001). EMPs in patients with CAL rapidly increased after the initial treatment, and was significantly higher than those in NCAL ( P  < 0.001). In patients with CAL, we identified 2 specific miRs encapsulated in EMPs, hsa-miR-145-5p and hsa-miR-320a, which are predicted to affect monocyte function using in silico analysis, and were demonstrated to upregulate inflammatory cytokine mRNAs in THP-1 monocytes. In situ hybridization confirmed that hsa-miR-145-5p was preferentially expressed in CAL. EMPs may serve as a sensitive marker for the severity of vasculitis in acute KD. Moreover, these 2 specific miRs encapsulated in EMPs might be involved in inflammatory cytokine regulation and the pathogenesis of vasculitis in acute KD.

BackgroundLeft ventricular noncompaction (LVNC) is a primary cardiomyopathy with heterogeneous genetic origins. The aim of this study was to elucidate the role of sarcomere gene variants in the pathogenesis and prognosis of LVNC.Methods and resultsWe screened 82 Japanese patients (0–35 years old), with a diagnosis of LVNC, for mutations in seven genes encoding sarcomere proteins, by direct DNA sequencing. We identified variants in a significant proportion of cases (27%), which were associated with poor prognosis (p = 0.012), particularly variants in TPM1, TNNC1, and ACTC1 (p = 0.012). To elucidate the pathological role, we developed and studied human-induced pluripotent stem cells (hiPSCs) from a patient carrying a TPM1 p.Arg178His mutation, who underwent heart transplantation. These cells displayed pathological changes, with mislocalization of tropomyosin 1, causing disruption of the sarcomere structure in cardiomyocytes, and impaired calcium handling. Microarray analysis indicated that the TPM1 mutation resulted in the down-regulation of the expression of numerous genes involved in heart development, and positive regulation of cellular process, especially the calcium signaling pathway.ConclusionsSarcomere genes are implicated as genetic triggers in the development of LVNC, regulating the expression of numerous genes involved in heart development, or modifying the severity of disease.

TBX5 is a transcription factor that has an important role in development of heart. TBX5 variants in the region encoding the T-box domain have been shown to cause cardiac defects, such as atrial septal defect or ventricular septal defect, while TBX5 variants have also been identified in a few cardiomyopathy patients and considered causative. We identified a TBX5 variant (c.791G>A, p.Arg264Lys), that is over-represented in cardiomyopathy patients. This variant is located outside of the T-box domain, and its pathogenicity has not been confirmed by functional analyses. To investigate whether the TBX5 R264K is deleterious and could contribute to the pathogenesis of cardiomyopathy. We developed mice expressing Tbx5 R264K. Mice homozygous for this variant displayed compensated dilated cardiomyopathy; mild decreased fractional shortening, dilatation of the left ventricle, left ventricular wall thinning and increased heart weight without major heart structural disorders. There was no difference in activation of the ANF promotor, a transcriptional target of Tbx5, compared to wild-type. However, analysis of RNA isolated from left ventricular samples showed significant increases in the expression of Acta1 in left ventricle with concomitant increases in the protein level of ACTA1. Mice homozygous for Tbx5 R264K showed compensated dilated cardiomyopathy. Thus, TBX5 R264K may have a significant pathogenic role in some cardiomyopathy patients independently of T-box domain pathway.

Background: Left ventricular noncompaction (LVNC) is a hereditary cardiomyopathy that is associated with high morbidity and mortality rates. Recently, LVNC was classified into several phenotypes including congenital heart disease (CHD). However, although LVNC and CHD are frequently observed, the role and clinical significance of genetics in these cardiomyopathies has not been fully evaluated. Therefore, we aimed to evaluate the impact on the perioperative outcomes of children with concomitant LVNC and CHD using next-generation sequencing (NGS). Methods: From May 2000 to August 2018, 53 Japanese probands with LVNC (25 males and 28 females) were enrolled and we screened 182 cardiomyopathy-associated genes in these patients using NGS. Results: The age at diagnosis of the enrolled patients ranged from 0 to 14 years (median: 0.3 months). A total of 23 patients (43.4%) were diagnosed with heart failure, 14 with heart murmur (26.4%), and 6 with cyanosis (11.3%). During the observation period, 31 patients (58.5%) experienced heart failure and 13 (24.5%) developed arrhythmias such as ventricular tachycardia, supraventricular tachycardia, and atrioventricular block. Moreover, 29 patients (54.7%) had ventricular septal defects (VSDs), 17 (32.1%) had atrial septal defects, 10 had patent ductus arteriosus (PDA), and 7 (13.2%) had Ebstein’s anomaly and double outlet right ventricle. Among the included patients, 30 underwent surgery, 19 underwent biventricular repair, and 2 underwent pulmonary artery banding, bilateral pulmonary artery banding, and PDA ligation. Overall, 30 genetic variants were identified in 28 patients with LVNC and CHD. Eight variants were detected in MYH7 and two in TPM1. Echocardiography showed lower ejection fractions and more thickened trabeculations in the left ventricle in patients with LVNC and CHD than in age-matched patients with VSDs. During follow-up, 4 patients died and the condition of 8 worsened postoperatively. The multivariable proportional hazards model showed that heart failure, LV ejection fraction of < 24%, LV end-diastolic diameter z-score of > 8.56, and noncompacted-to-compacted ratio of the left ventricular apex of > 8.33 at the last visit were risk factors for survival. Conclusions: LVNC and CHD are frequently associated with genetic abnormalities. Knowledge of the association between CHD and LVNC is important for the awareness of clinical implications during the preoperative and postoperative periods to identify the populations who are at an increased risk of additional morbidity.

Background Left ventricular noncompaction cardiomyopathy (LVNC) is characterized by prominent ventricular trabeculations on cardiovascular imaging. Acquired reversible LVNC has not been reported in pediatrics without a genetic background. Case presentation A 9-year-old girl with a ventriculoperitoneal (VP) shunt for neonatal posthemorrhagic hydrocephalus was referred due to exacerbation of hydrocephalus caused by VP shunt dysfunction. Transthoracic echocardiography (TTE) revealed depressed left ventricular (LV) systolic function and thick prominent trabeculae in the LV, predominantly in the apex, suggesting LVNC. Following treatment with extraventricular drainage for hydrocephalus, prominent trabeculation of the LV was diminished on TTE within 3 months. Genetic testing using next-generation sequencing was performed, and no significant variants were identified. Conclusions We revealed for the first time a pediatric case of reversible LVNC without genetic predisposition. This case report provides valuable information on the pathogenesis of acquired LVNC and suggests that detailed evaluation is required to elucidate the diagnosis of this wide spectrum of etiologic–pathogenetic disorders.

Background/Objectives: Remote dielectric sensing (ReDS) is a recently developed, noninvasive, electromagnetic energy-based technology designed to quantify pulmonary congestion without requiring expert techniques in adult patients with heart failure. However, its applicability in pediatric patients remains unknown. Methods: ReDS values and chest X-rays were simultaneously obtained from pediatric patients with a history of Fontan surgery at an outpatient clinic. The Congestion Severity Index (CSI) was calculated from chest X-rays to analyze its correlation with ReDS values. Results: A total of 21 pediatric patients (median age: 17 years; median height: 152.7 cm; median weight: 48.6 kg; 12 male patients) were included. ReDS values were successfully measured in all participants without any measurement failure. A mild correlation was observed between ReDS values and CSIs (r = 0.47, p = 0.030). In patients with ReDS values exceeding 35% (N = 11), a stronger correlation was noted between ReDS values and CSIs (r = 0.61, p = 0.046). In patients with ReDS values ≤ 35% (N = 10), ReDS values exhibited a wide distribution (25% to 35%) despite low CSI values. Conclusions: The ReDS system demonstrates potential as a feasible technology for the noninvasive quantification of pulmonary congestion in pediatric patients, irrespective of the severity of congestion. Notably, the ReDS system may have the potential to identify subclinical pulmonary congestion in pediatric patients with heart failure.

Background: Left ventricular hypertrophy (LVH) is a well-recognized cardiac dysfunction in infants of mothers with gestational diabetes mellitus (GDM). Left ventricular noncompaction (LVNC) is a cardiomyopathy that is morphologically characterized by numerous prominent trabeculations and deep intertrabecular recesses on cardiovascular imaging. However, there have been no case reports on neonates of mothers with GDM showing LVH and LVNC. Case presentation: A patient, with LVH of a mother with GDM, was delivered at 36 weeks of gestation. Prominent trabeculations in the LV, suggesting LVNC, instead of LVH, were apparent 1 week after birth. A heterozygous deletion variant in the MYH7 gene (NM_000257.4: c.1090T>C, p.Phe364Leu) was discovered through genetic testing using a cardiomyopathy-associated gene panel in the patient and his father and the older brother who had LVNC. The patient is now 5 years old and does not have major cardiac events, although LVNC persisted. This is the first case of LVH secondary to a mother with GDM and LVNC with a novel variant in the MYH7 gene. Conclusion: Genetic testing should be conducted to obtain an accurate outcome and medical care in a patient with LVH and subsequently prominent hypertrabeculation in the LV.