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Background Left ventricular noncompaction (LVNC) is morphologically characterized by numerous prominent trabeculations and a severely thickened, two-layered myocardium. The fetal onset of LVNC has rarely been described.Methods and Results:We conducted nationwide retrospective surveys on fetal cardiomyopathy (CM) in Japan from 2010 to 2016, from which 38 fetal patients with CM were enrolled, including 16 patients with LVNC. The rate of diagnostic concordance was 56.3% between fetal and postnatal visits in LVNC patients. The increase in the ratio of noncompacted to compacted (N/C) myocardium was time-dependent throughout the fetal period till birth (LV lateral: 1.6±0.1 to 2.8±0.2; LV apex: 2.0±0.1 to 3.2±0.2). Of all fetuses, 16 (42.1%) died or underwent heart transplantation (HT), with 3 intrauterine deaths. Lower fetal cardiovascular profile score (odds ratio, 26.9; P=0.0266) was a risk factor for death or HT. N/C ratio ≥1.6 at the apex at the first visit was a significant predictor of LVNC (odds ratio, 47.8; P=0.0113). Conclusions This is the first study to reveal the etiology of fetal CM based on results from a nationwide survey in Japan, highlighting the difficulty of diagnosing LVNC in fetal patients. To better understand and manage fetal CM, novel diagnostic criteria of LVNC in fetus should be established.

Left ventricular noncompaction (LVNC) is a hereditary cardiomyopathy and is associated with high morbidity and mortality. However, the role and significance of school screening for LVNC have not been fully elucidated. In this multicenter, retrospective cohort study, a total of 105 children with LVNC were included from 2000 to 2017. At the initial presentation, 44 patients (41.9%) were diagnosed by school screening. One (1.0%) patient underwent heart transplantation and four (3.8%) patients died during the study. Electrocardiogram data showed a high prevalence of fragmented QRS (33.4%) and J wave (15.7%). Treatments were needed in eight (18.2%) patients who were detected by school screening. The multivariable proportional hazards model showed T-wave abnormality on electrocardiogram in first graders was independent risk factors for major adverse cardiac events (odds ratio 4.94, p value = 0.0007). Moreover, dilation of the left atrium on chest X-ray and low ejection fraction on echocardiogram at the initial treatment were independent risk factors for treatment (odds ratio 1.7 × 107 and 22.3, p = 0.0362 and 0.0028, respectively). This study is the first report focusing on school screening in a large pediatric cohort with LVNC. With the use of abnormalities in electrocardiogram, school screening may be a good detector of and predictor for LVNC.

ObjectiveLeft ventricular non-compaction (LVNC) is morphologically characterised by excessive trabeculations and deep recesses in the ventricular wall. The risk of thromboembolic disease in the paediatric patients with LVNC has not been clearly established. We conducted this systematic review to evaluate the prevalence and incidence of thromboembolism (TE) in paediatric and adult patients with LVNC and searched for risk factors for TE to explore management strategies.MethodsThe primary outcome was the prevalence and incidence of TE in the patients with LVNC. The secondary outcome was the TE and mortality and heart transplantation rates between paediatric and adult patients with LVNC. We searched for studies published in MEDLINE, Embase and Cochrane Central Register of Controlled Trials between January 1950 and December 2020. A systematic search of keywords related to LVNC, anticoagulants/antiplatelets and TE was conducted. Studies that did not present original research, non-human studies, duplicated studies were excluded.ResultsFifty-seven studies met the inclusion criteria. A total of 726 paediatric and 3862 adult patients were included. The mean prevalence rates of TE in the paediatric and adult patients with LVNC were 2.6% and 6.2% (I2=0%; p2=73.7%; p2=99.4%; p2=99.5%; pConclusionsThe prevalence and incidence rates in paediatric patients were lower than those in adult patients. TE was associated with a reduced systolic function in paediatric patients with LVNC.

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.

Kawasaki 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.A 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.About 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 and0.0001, 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.This study uncovered the crucial role of lncRNAs in innate immunity in acute KD. LncRNA may be a novel target for the diagnosis of KD.This 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.

Background: Left ventricular noncompaction (LVNC) is a hereditary type of cardiomyopathy. Although it is associated with high morbidity and mortality, the related ion channel gene variants in children have not been fully investigated. This study aimed to elucidate the ion channel genetic landscape of LVNC and identify genotype-phenotype correlations in a large Japanese cohort. Methods: We enrolled 206 children with LVNC from 2002 to 2017 in Japan. LVNC was classified as follows: LVNC with congenital heart defects, arrhythmia, dilated phenotype, or normal function. In the enrolled patients, 182 genes associated with cardiomyopathy were screened using next-generation sequencing. Results: We identified 99 pathogenic variants in 40 genes in 87 patients. Of the pathogenic variants, 8.8% were in genes associated with channelopathies, 27% were in sarcomere genes, and 11.5% were in mitochondrial genes. Ion channel gene variants were mostly associated with the arrhythmia classification, whereas sarcomere and mitochondrial gene variants were associated with the dilated phenotype. Echocardiography revealed that the group with ion channel gene variants had almost normal LV ejection fraction and LV diastolic diameter Z scores. Fragmented QRS, old age, and an arrhythmia phenotype were the most significant risk factors for ventricular tachycardia ( P =0.165, 0.0428, and 0.0074, respectively). Moreover, the group with ion channel variants exhibited a greater risk of a higher prevalence of arrhythmias such as ventricular tachycardia, rather than congestive heart failure. Conclusions: This is the first study that focused on genotype-phenotype correlations in a large pediatric LVNC patient cohort with ion channel gene variants that were determined using next-generation sequencing. Ion channel gene variants were strongly correlated with arrhythmia phenotypes. Genetic testing and phenotype specification allow for appropriate medical management of specific LVNC targets.

Background Left ventricular noncompaction (LVNC) is a hereditary cardiomyopathy, associated with high morbidity and mortality, but the role of genetics in cases of fetal-onset has not been fully evaluated. The goal of this study was to identify the genetic background in LVNC fetal-onset patients using next-generation sequencing (NGS). Methods Thirty-three fetal-onset Japanese probands with LVNC (20 males and 13 females) were enrolled. In the enrolled patients, 81 genes associated with cardiomyopathy were screened using next-generation sequencing (NGS) retrospectively. Results Twenty-three patients had congestive heart failure (CHF), and six patients had arrhythmias. Prominent trabeculations were mostly observed in lateral LV, posterior LV, and apex of LV in patients with LVNC. Twelve died; three patients experienced intrauterine death or termination of pregnancy. Overall, 15 variants were found among eight genes in 16 patients. Seven variants were detected in MYH7 and two in TPM1. Sarcomere gene variants accounted for 75.0%. A multivariable proportional hazards model revealed that CHF at diagnosis and a higher ratio of the noncompacted layer/compacted layer in the LV posterior wall were independent risk factors for death in LVNC fetal-onset patients (odds ratio = 4.26 × 106 and 1.36 × 108, p = 0.0075 and 0.0005, respectively). Conclusions The present study is the first report focusing on genetic background combined with clinical features in LVNC fetal-onset patients using NGS. Sarcomere variants were most commonly identified in fetal-onset patients, and greater attention should be paid to fetal-onset patients with LVNC having prominent trabeculations in the LV because they are more likely to develop CHF.

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 &lt, 24%, LV end-diastolic diameter z-score of &gt, 8.56, and noncompacted-to-compacted ratio of the left ventricular apex of &gt, 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.

BackgroundTBX5 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.ObjectiveTo investigate whether the TBX5 R264K is deleterious and could contribute to the pathogenesis of cardiomyopathy.Methods and resultsWe 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.ConclusionsMice 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 The natural history of left ventricular noncompaction (LVNC) is largely unsolved, so the aim of the present study was to clarify the clinical features and long-term prognosis of children with LVNC until adulthood.Methods and Results:We conducted a nationwide survey over 20 years and compared the clinical features, anatomical characteristics and long-term prognosis of 205 patients divided into 2 classifications: infantile type (diagnosed at

Kawasaki disease (KD) is the most common systemic vasculitis syndrome primarily affecting medium-sized arteries, particularly the coronary arteries. Though KD may be associated with immunological problems, the involvement of microRNAs (miRs) has not been fully described. We enrolled 23 KD patients and 12 controls. We performed miR and mRNA microarray analysis of peripheral blood mononuclear cells (PBMCs) isolated from acute KD patients and controls. Continuously, we measured specific miRs, mRNA and the expression of proteins by using reverse-transcriptase PCR (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). We identified strikingly high levels of miR-182 and miR-296-5p during the acute febrile phase, and of miR-93, miR-145-5p, miR-145-3p, and miR-150-3p in the defervescence stage, especially in refractory KD patients. The expression of vascular endothelial growth factor A (VEGFA) mRNA, previously reported to be controlled by miR-93, was significantly elevated during the febrile phase and normalized upon treatment, negatively correlating with the expression of miR-93. Further, plasma levels of VEGF-A correlated with PBMC VEGFA mRNA expression. Several miRs are highly specific to the acute phase of KD, and may participate in regulating the expression of genes in pathways associated with KD. In particular, miR-93 may participate in regulating expression of VEGF-A and contribute to the pathogenesis of arteritis in acute KD.

Left 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. We 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. Sarcomere 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.