G0S2 regulates innate immunity in Kawasaki disease via lncRNA HSD11B1-AS1.

BACKGROUND: 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. METHODS: 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. RESULTS: 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 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. CONCLUSIONS: 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. IMPACT: 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.

Clinical significance of chronic myocarditis: systematic review and meta-analysis.

Chronic myocarditis is a prolonged inflammatory condition in the myocardium and its histological manifestation is defined by the presence of an inflammatory infiltrate. Chronic myocarditis has not been well known and its treatment of chronic myocarditis has not been established. Primary outcome of this study was to assess the efficacy of immunomodulatory treatment in addition to conventional treatment, and secondary outcomes were to clarity the prognosis of natural history of chronic myocarditis and incidence of chronic myocarditis in patients with dilated cardiomyopathy (DCM). We searched for studies in Medline, Embase, Cochrane Central Register of Controlled Trials, and Igaku Chuo Zasshi published between January 1946 and June 2020. Sixteen studies met the inclusion criteria. A meta-analysis revealed that patients receiving immunomodulatory treatment showed an improvement in left ventricular ejection fraction after immunomodulatory treatment compared to the control group (hazard ratio, 16.65; confidence interval, 4.55-28.74; p = 0.007). Five-year survival rate of the patients with inflammatory DCM (iDCM) and DCM was 52.7-70.3% and 51.9-91.1%, respectively. Moreover, 51.5%-62.7% of patients with DCM met the criteria of iDCM. Our systematic review revealed that patients with chronic myocarditis had poor prognosis and immunomodulatory treatment was significantly effective in addition to conventional treatment.

Clinical Characteristics and Prognosis of Fetal Left Ventricular Noncompaction in Japan.

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.

Reversible left ventricular noncompaction caused by hypertensive hydrocephalus: a pediatric case report.

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.

Perforated posterior mitral leaflet aneurysm in an 8-month-old infant.

Mitral valve aneurysm not associated with infective endocarditis is rarely reported in children. We report a case of perforated posterior mitral leaflet aneurysm in an infant with reference to surgical and histopathological findings. Although its aetiology remains unclear, we suggest to include mitral valve aneurysm in differential diagnosis as a cause of mitral regurgitation in children.

Neurodevelopmental outcomes at 3 years for infants with congenital heart disease and very-low birthweight.

BACKGROUND: Both congenital heart disease (CHD) and very-low birthweight (VLBW) infants are at a very high risk of neurodevelopmental delay. We investigated neurological development at 3 years in pediatric patients with CHD after surgical intervention, those of VLBW, and healthy controls. METHODS: We enrolled pediatric patients with CHD (n = 67), VLBW (n = 67), and healthy controls (n = 81). Infants with CHD were grouped into those with single ventricle and two ventricles, and infants with VLBW were grouped into those with birthweights of <1000 and 1000-1499 g. Neurodevelopmental outcomes at 3 years were evaluated using the Bayley Scales of Infant and Toddler Development, Third Edition. RESULTS: Compared with healthy controls, a significant deficit in the language, cognition, and motor skills scores were observed in infants with CHD and VLBW. Infants with a single ventricle exhibited significantly low scores in language and gross motor skills. No statistically significant difference was observed between the birthweight groups of <1000 and 1000-1499 g. CONCLUSION: Neurodevelopmental outcomes for infants with both CHD and VLBW showed impairment. Notably, neurodevelopmental delays in infants with a single ventricle were remarkable. Thus, because infants with both CHD and VLBW are at high risk of neurodevelopmental disorders, periodic developmental screenings and support are warranted for these children.

[Redo Right Ventricular Outflow Tract Reconstruction in Adult Patients with Congenital Heart Disease].

Between April 2005 and February 2019, 11 adult patients underwent redo reconstruction of the right ventricular outflow tract. The primary malformation was Fallot's tetralogy in 8, transposition of the great arteries in 2, and pulmonary atresia with intact ventricular septum in 1. Mean age at redo operation was 27.4 years. Right ventricular outflow tract was reconstructed with expanded polytetrafluoroethylene conduits with bulging sinuses and a fan-shaped valve in 9, transannular patch in 1, and right ventricular outflow patch in 1. There were no early and late deaths. One patient had residual branch pulmonary stenosis, while other 10 patients had no significant pulmonary stenosis and no significant pulmonary regurgitation. Signs and symptoms were improved in these 10 patients. Re-operation should be done before the development of right ventricular dysfunction, while it can be performed with satisfactory results in adult patients.

Sarcomere gene variants act as a genetic trigger underlying the development of left ventricular noncompaction.

BACKGROUND: 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. METHODS AND RESULTS: 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. CONCLUSIONS: 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.

Clinical and Echocardiographic Impact of Tafazzin Variants on Dilated Cardiomyopathy Phenotype in Left Ventricular Non-Compaction Patients in Early Infancy.

BACKGROUND: Left ventricular non-compaction (LVNC) is a cardiomyopathy morphologically characterized by 2-layered myocardium and numerous prominent trabeculations, and is often associated with dilated cardiomyopathy (DCM). Variants in the gene encoding tafazzin (TAZ) may change mitochondrial function and cause dysfunction of many organs, but they also contribute to the DCM phenotype in LVNC, and the clinical and echocardiographic features of children with this phenotype are poorly understood. Methods and Results: We enrolled 92 DCM phenotype LVNC patients and performed next-generation sequencing to identify the genetic etiology. Ten TAZ variants were identified in 15 male patients (16.3%) of the 92 patients, including 3 novel missense substitutions. The patients with TAZ variants had a higher frequency of early onset of disease (92.3% vs. 62.3%, P=0.0182), positive family history (73.3% vs. 20.8%, P=0.0001), and higher LV posterior wall thickness Z-score (8.55±2.60 vs. 5.81±2.56, P=0.0103) than those without TAZ variants, although the mortality of both groups was similar. CONCLUSIONS: This study provides new insight into the impact of DCM phenotype LVNC and emphasizes the clinical advantages available for LVNC patients with TAZ variants.

Long-Term Prognosis of Patients With Left Ventricular Noncompaction　- Comparison Between Infantile and Juvenile Types.

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 <1 year of age: 108 cases) and juvenile type (diagnosed 1-15 years of age: 97 cases). Most patients diagnosed during infancy had heart failure (HF) at initial presentation (60.19%), while the majority of juvenile cases were asymptomatic (53.61%) but their event-free survival rate decreased gradually, because of later HF, thromboembolism and fatal arrhythmias. The initial LVEF was significantly lower in the infantile type and correlated with the thickness of the compacted layer in the LV posterior wall (LVPWC) and LV end-diastolic dimension (LVDD) Z-score, but not to the noncompacted to compacted layer (N/C) ratio. Survival analysis showed prognosis was similarly poor for both types after 2 decades. The significant risk factors for death, heart transplantation or implantable cardioverter-defibrillator insertion were congestive HF at diagnosis and lower LVPWC Z-score but not age of onset. CONCLUSIONS: LVNC of both types showed poor long-term prognosis, therefore ongoing follow-up is recommended into adulthood. HF at diagnosis and LVPWC hypoplasia are major determinants of poor prognosis.

MicroRNA-93 may control vascular endothelial growth factor A in circulating peripheral blood mononuclear cells in acute Kawasaki disease.

BACKGROUND: 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. METHODS: 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). RESULTS: 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. CONCLUSION: 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.

Evaluation of right ventricular function using single-beat three-dimensional echocardiography in neonate.

Aim of our study was to evaluate right ventricular (RV) systolic function in neonate using newly developed single-beat three-dimensional echocardiography (sb3DE). We enrolled 15 healthy or premature neonates (0-53 days after birth). We scanned one beat full volume using Siemens ACUSON SC2000 (Siemens AG) echocardiography with 4Z1c full-volume transducer without ECG gating. RV end-diastolic volume (RVEDV) and RV end-systolic volume (RVESV) were computed with special software dedicated to analysis for RV volume. RV ejection fraction (RVEF) and RV stroke volume (3D-RVSV) were calculated. And RV stroke volume was also determined from the recordings of ejection blood flow velocity and diameter at the level of the pulmonary orifice in RV outflow tract (Doppler-RVSV). Tricuspid annular plane systolic excursion (TAPSE) was also measured by 2D echocardiography. RVEDV ranged from 5.1 to 10.7 ml (average 7.5 ml), RVESV ranged from 2.3 to 5.8 ml (average 3.9 ml). There was a good correlation between 3D-RVSV and Doppler-RVSV (r = 0.77). Bland-Altman plot revealed that 3D-RVSV became underestimation of an average of 1.78 ml compared to Doppler-RVSV. And TAPSE positively correlated with 3D-RVEF (r = 0.58, P = 0.038). Newly developed sb3DE enables us to perform three-dimensional acquisition of RV volume without ECG gating even in neonate. However, 3D-RVSV currently tends to be underestimated in neonatal measurement.

Percutaneous catheter aspiration thrombectomy for the occluded stents of pulmonary artery in children with single ventricle physiology after fontan surgery.

Successful surgical palliation with the Fontan procedure allows survival into adulthood for many patients born with single ventricle (SV) physiology, but the limited studies reported incidence of perioperative and long-term complications including thromboembolic events. Chronic pulmonary embolism is a common complication in patients with Fontan circulation, and may have serious consequences. Percutaneous intervention may be less invasive option for such a high-risk population than surgery is. We described two patients who developed complete thrombosis of the left pulmonary artery following catheter placement of a stent in this vessel shortly after Fontan surgery. Percutaneous catheter aspiration thrombectomy was successfully performed. Percutaneous catheter aspiration thrombectomy may be considered as a viable option in acute thrombus in children with SV physiology after Fontan surgery.

N-terminal pro-brain natriuretic peptide as a predictor of reoperation in children with surgically corrected tetralogy of fallot.

BACKGROUND: Most patients with surgically corrected tetralogy of Fallot (TOF) are faced with multiple residua and sequelae such as pulmonary regurgitation (PR), resulting in reoperation for pulmonary valve replacement (PVR). Plasma brain natriuretic peptide (BNP) level and serum N-terminal pro-BNP (NT-pro-BNP) level are useful as diagnostic objective markers of chronic heart failure (CHF). The aim of the study was to examine whether these markers have predictive ability for reoperation in children with surgically corrected TOF. METHODS AND RESULTS: Fifty-eight patients (38 male, 20 female) aged 1-18 years (median, 7 years) were enrolled. Serum NT-pro-BNP in TOF patients was significantly higher than in age-matched hospital controls without CHF (359.5±449.7pg/ml vs. 86.1±45.1pg/ml, respectively; P<0.0001). BNP and NT-pro-BNP had a better correlation with CHF index, RVEDP, and LVEDV in TOF groups. Children with surgically corrected TOF who had indication for PVR had higher BNP and NT-pro-BNP and more severe PR than those without indication for PVR. On multivariate logistic regression analysis, NT-pro-BNP was the strongest predictor for reoperation in patients with surgically corrected TOF. Area under the curve of NT-pro-BNP for reoperation was 0.950 (P<0.001) with a sensitivity of 88.9% and specificity of 91.8%. CONCLUSIONS: NT-pro-BNP is a good biomarker for monitoring CHF, and is a good predictor of PVR in children with surgically repaired TOF.

Tachycardia-Induced Cardiomyopathy in an Infant with Atrial Flutter and Prolonged Recovery of Cardiac Function.

Background: Tachycardia-induced cardiomyopathy (TIC) is caused by prolonged tachycardia, leading to left ventricular dilatation and systolic dysfunction with heart failure. Although TIC is more common in adults, it is rare in early infancy. Methods: Clinical testing was performed as part of medical evaluation and management. Next-generation sequencing (NGS) was conducted for a patient with TIC. A literature review on TIC was also conducted. Results: The case involved a 5-month-old infant referred to the hospital due to symptoms of heart failure lasting at least two months. The infant's heart rate was 200 beats per minute, the left ventricular ejection fraction fell below 14%, and electrocardiograms showed atrial flutter, suggesting TIC. After cardioversion, there was no recurrence of atrial flutter, and cardiac function improved 98 days after tachycardia arrest. The NGS did not identify any pathogenic variants. The literature review identified eight early infantile cases of TIC. However, no previous reports described a case with such a prolonged duration of TIC as ours. Conclusions: This is the first report of a case of prolonged TIC in a child with the documented time to recover normal cardiac function. The improvement of cardiac function depends on the duration of TIC. Early recognition and intervention in TIC are essential to improve outcomes for infantile patients, as timely treatment offers the potential for recovery.

Novel MYH7 Variant in the Neonate of a Mother with Gestational Diabetes Mellitus Showing Left Ventricular Hypertrophy and Noncompaction.

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.

Serum Angiopoetin-2 Levels in Pediatric Patients After Fontan Operation.

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.

Optimal Heart Rate May Improve Systolic and Diastolic Function in Patients with Fontan Circulation.

(1) Background: The optimal heart rate, at which the E-wave and A-wave stand adjacent without any overlaps in the Doppler transmitral flow echocardiography, is associated with maximum cardiac output and favorable clinical outcomes in adult patients with systolic heart failure. However, the clinical implication of the echocardiographic overlap length in patients with Fontan circulation remains unknown. We investigated the relationship between heart rate (HR) and hemodynamics in Fontan surgery patients with and without beta-blockers. (2) Methods and Results: A total of 26 patients (median age 1.8 years, 13 males) were enrolled. At baseline, the plasma N-terminal pro-B-type natriuretic peptide was 2439 ± 3483 pg/mL, the fraction area change was 33.5 ± 11.4%, the cardiac index was 3.55 ± 0.90 L/min/m2, and the overlap length was 45.2 ± 59.0 msec. Overlap length was importantly decreased after the one-year follow-up (7.60 ± 78.57 msec, p = 0.0069). Positive correlations were noted between the overlap length and A-wave and E/A ratio (p = 0.0021 and p = 0.0046, respectively). Ventricular end-diastolic pressure was significantly correlated with the overlap length in non-beta-blocker patients (p = 0.0483). (3) Conclusion: Overlap length may reflect the status of ventricular dysfunction. Hemodynamic preservation at lower HR could be critical for cardiac reverse remodeling.

Thromboembolic events in left ventricular non-compaction: comparison between children and adults - a systematic review and meta-analysis.

OBJECTIVE: Left 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. METHODS: The 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. RESULTS: Fifty-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%; p<0.450 and I2=73.7%; p<0.001), respectively. The mean annual incidences of TE in paediatric and adult patients with LVNC were 1.4% and 2.9% (I2=99.4%; p<0.001 and I2=99.5%; p<0.001), respectively. Multivariate logistic regression analysis showed that TE was associated with left ventricular ejection fraction in <40% of paediatric patients (OR, 9.47; 95% CI, 1.35 to 188.23; p=0.0225). CONCLUSIONS: The 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.