Association between the initiation of insurance coverage for fetal echocardiography and mortality from congenital heart disease in infants: An interrupted time series analysis.

BACKGROUND: The effectiveness of fetal echocardiography in reducing the mortality from congenital heart disease (CHD) is largely unknown. OBJECTIVES: This study aimed to evaluate whether the widespread use of fetal echocardiography owing to the initiation of insurance coverage in Japan was associated with a decreasing trend in the annual number of CHD-related deaths. METHODS: Data regarding the number of deaths from CHD in infants aged <12 months were extracted from Japanese demographic statistics (2000-2018). Segmented regression analysis was performed on the interrupted time series data by stratifying the sample into CHD subgroups based on ICD-10 classification and sex. RESULTS: After the initiation of insurance coverage for fetal echocardiography in 2010, a decrease was observed in the trends of annual deaths in patients with congenital malformations of aortic and mitral valves (ratio of trends before and after the initiation of insurance coverage for fetal echocardiography 0.96, 95% confidence interval 0.93, 0.99). In this group, the decrease persisted after adjusting for annual total infant deaths and cardiac surgery mortality and in the analysis of trends in the proportion of deaths in this group per total CHD deaths. However, a decrease in trends was not observed in other patient groups with CHD. In the sex-stratified analysis, a decrease was noted only in male patients with congenital malformations of aortic and mitral valves. CONCLUSIONS: The nationwide trend in annual CHD deaths decreased after the initiation of insurance coverage for fetal echocardiography only among patients with congenital malformation of aortic and mitral valves. These findings suggest that prenatal diagnosis with fetal echocardiography has led to improved mortality outcomes among these patients in Japan.

The Anti-Inflammatory Effects and Clinical Potential of Dexmedetomidine in Pulmonary Arterial Hypertension.

A pathogenic aspect of pulmonary arterial hypertension (PAH) is the aberrant pulmonary arterial smooth muscle cell (PASMC) proliferation. PASMC proliferation is significantly affected by inflammation. A selective α-2 adrenergic receptor agonist called dexmedetomidine (DEX) modulates specific inflammatory reactions. We investigated the hypothesis that anti-inflammatory characteristics of DEX could lessen PAH that monocrotaline (MCT) causes in rats. In vivo, male Sprague-Dawley rats aged 6 weeks were subcutaneously injected with MCT at a dose of 60 mg/kg. Continuous infusions of DEX (2 µg/kg per hour) were started via osmotic pumps in one group (MCT plus DEX group) at day 14 following MCT injection but not in another group (MCT group). Right ventricular systolic pressure (RVSP), right ventricular end-diastolic pressure (RVEDP), and survival rate significantly improved in the MCT plus DEX group compared with the MCT group [RVSP, 34 mmHg ± 4 mmHg versus 70 mmHg ± 10 mmHg; RVEDP, 2.6 mmHg ± 0.1 mmHg versus 4.3 mmHg ± 0.6 mmHg; survival rate, 42% versus 0% at day 29 (P < 0.01)]. In the histologic study, the MCT plus DEX group showed fewer phosphorylated p65-positive PASMCs and less medial hypertrophy of the pulmonary arterioles. In vitro, DEX dose-dependently inhibited human PASMC proliferation. Furthermore, DEX decreased the expression of interleukin-6 mRNA in human PASMCs treated with fibroblast growth factor 2 (FGF2). These consequences suggest that DEX improves PAH by inhibiting PASMC proliferation through its anti-inflammatory properties. Additionally, DEX may exert anti-inflammatory effects via blocking FGF2-induced nuclear factor κ B activation. SIGNIFICANCE STATEMENT: Dexmedetomidine, a selective α-2 adrenergic receptor agonist utilized as a sedative in the clinical setting, improves pulmonary arterial hypertension (PAH) by inhibiting pulmonary arterial smooth muscle cell proliferation through its anti-inflammatory effect. Dexmedetomidine may be a new PAH therapeutic agent with vascular reverse remodeling effect.

Electrocardiographic Diagnosis of Hypertrophic Cardiomyopathy in the Pre- and Post-Diagnostic Phases in Children and Adolescents.

BACKGROUND: The usefulness of electrocardiographic (ECG) voltage criteria for diagnosing hypertrophic cardiomyopathy (HCM) in pediatric patients is poorly defined.Methods and Results:ECGs at the 1st grade (mean [±SD] age 6.6±0.3 years) were available for 11 patients diagnosed with HCM at around the 7th grade (13.2±0.3 years). ECGs were available for another 64 patients diagnosed with HCM in the 1st (n=15), 7th (n=32), and 10th (n=17) grades. Fifty-one voltage criteria were developed by grade and sex using 62,841 ECGs from the general population. Voltage criteria were set at the 99.95th percentile (1/2,000) point based on the estimated prevalence of childhood HCM (2.9 per 100,000 [1/34,483]) to decrease false negatives. Conventional criteria were from guidelines for school-aged children in Japan. Of 11 patients before diagnosis, 2 satisfied conventional criteria in 1st grade; 5 (56%) of the remaining 9 patients fulfilled 2 voltage criteria (R wave in limb-lead I [RI]+S wave in lead V3 [SV3] and R wave in lead V3 [RV3]+SV3). Robustness analysis for sensitivity showed RV3+SV3 was superior to RI+SV3. For all patients after diagnosis, RI+SV4 was the main candidate. However, conventional criteria were more useful than voltage criteria. CONCLUSIONS: Early HCM prediction was possible using RV3+SV3 in >50% of patients in 1st grade. Voltage criteria may help diagnose prediagnostic or early HCM, and prevent tragic accidents, although further prospective studies are required.

Novel electrocardiographic criteria for short QT syndrome in children and adolescents.

AIMS: Although shortening of the corrected QT interval (QTc) is a key finding in the diagnosis of short QT syndrome (SQTS), there may be overlap of the QTc between SQTS patients and normal subjects in childhood and adolescence. We aimed to investigate electrocardiographic findings for differentiation of SQTS patients. METHODS AND RESULTS: The SQTS group comprised 34 SQTS patients <20 years old, including 9 from our institutions and 25 from previous reports. The control group comprised 61 apparently healthy subjects with an QTc of <360 ms who were selected from 13 314 participants in a school-based screening programme. We compared electrocardiographic findings, including QT and Jpoint-Tpeak intervals (QT and J-Tpeak, respectively), those corrected by using the Bazett's and Fridericia's formulae (cB and cF, respectively) and early repolarization (ER) between the groups. QT, QTc by using Bazett's formula (QTcB), QTc by using Fridericia's formula (QTcF), J-Tpeak, J-Tpeak cB, and J-Tpeak cF were significantly shorter in the SQTS group than in the control group. On receiver operating characteristic curve analysis, the area under the curve (AUC) was largest for QTcB (0.888) among QT, QTcB, and QTcF, with a cut-off value of 316 ms (sensitivity: 79.4% and specificity: 96.7%). The AUC was largest for J-Tpeak cB (0.848) among J-Tpeak, J-Tpeak cB, and J-Tpeak cF, with a cut-off value of 181 ms (sensitivity: 80.8% and specificity: 91.8%). Early repolarization was found more frequently in the SQTS group than in the control group (67% vs. 23%, P = 0.001). CONCLUSION: A QTcB <316 ms, J-Tpeak cB < 181 ms, and the presence of ER may indicate SQTS patients in childhood and adolescence.

Diagnostic value of P-waves in children with idiopathic restrictive cardiomyopathy.

Restrictive cardiomyopathy (RCM) is a rare myocardial disease with an impaired diastolic function and poor prognosis. Almost all RCM patients are reported to have abnormal P-waves due to atrial overloading. This study aimed to reveal the characteristics of the P-waves in RCM patients and to suggest the diagnostic index of RCM in children with a 12-lead electrocardiogram (ECG). We retrospectively investigated 17 ECGs of children with idiopathic RCM during the initial visit at 15 institutes in Japan between 1979 and 2013. The RCM group was divided into four groups based on the age (elementary school [ES] and junior high school [JHS] students) and inception of the diagnosis (abnormal ECG on school-heart-screening [e-RCM] and some cardiovascular symptoms [s-RCM]), the ES/e-RCM (n = 5), ES/s-RCM (n = 4), JHS/e-RCM (n = 4), and JHS/s-RCM (n = 4) groups. As an aged-match control group, school-heart-screening ECGs of 1st-grade ES students (16,770 students) and 1st-grade JHS students (18,126 students) from Kagoshima in 2016 were adopted. For a comparison between the groups, we used the effect size "Hedge's g" by calculating the mean and standard deviation of the two groups. An effect size of 0.8 (or above) had an overlap of 53% (or less). The effect sizes of the sum of the absolute values of the forward and backward amplitudes in lead V1 (P1 + P2 V1) was the largest, and the ES/e-RCM, ES/s-RCM, JHS/e-RCM, and JHS/s-RCM were 15.8, 22.1, 9.4, and 10.3, respectively. A P1 + P2 V1 > 200 µV was able to rule in all RCM patients, thus, we proposed 200 µV as the cutoff value for screening purposes. In conclusion, the P1 + P2 V1 in the school-heart-screening may be useful for detecting asymptomatic or early-stage RCM in school-age children.

Impact of the T-wave characteristics on distinguishing arrhythmogenic right ventricular cardiomyopathy from healthy children.

BACKGROUND: T-wave inversion (TWI) is not considered useful for diagnosing pediatric arrhythmogenic right ventricular cardiomyopathy (ARVC), because right precordial TWI in ARVC resembles a normal juvenile pattern. OBJECTIVES: The aims of this study were to clarify the electrocardiographic (ECG) characteristics of pediatric ARVC to distinguish those patients from healthy children. METHODS: Between 1979 and 2017, 11 ARVC patients under 18 years old were registered and compared with school screening ECGs from 48,401 healthy children. RESULTS: The mean age at the first arrhythmic event or diagnosis was 13.3 ± 4.7 years. Nine patients were asymptomatic initially and were found by ECG screening, but 6 developed severe symptoms during the follow-up. Healthy children had a normal juvenile pattern, while ARVC children, especially symptomatic patients, had a significant tendency to have inferior and anterior TWI. The phenomenon of T-wave discontinuity (TWD) in which the TWI became deeper from V1 to V3 and suddenly turned positive in V5 was significantly more frequent in ARVC (60%) than healthy children (0.55%). Anterior TWI and TWD were also significantly more frequent in those who developed severe symptoms. The sensitivity and specificity of TWD were 60% (95% CI, 31-83%), and 99% (95% CI, 99-99%) to distinguish ARVC from healthy children, as well as 100% (95% CI, 71-100%) and 80% (95% CI, 51-80%), respectively, to predict severe symptoms in the future. CONCLUSIONS: The ECG is useful to distinguish ARVC children, even in the early phase. Anterior TWI and TWD could detect ARVC children and to predict the possible serious conditions.

A significance of school screening electrocardiogram in the patients with ventricular noncompaction.

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.

WDR11 is another causative gene for coloboma, cardiac anomaly and growth retardation in 10q26 deletion syndrome.

10q26 deletion syndrome is caused by a rare chromosomal abnormality, and patients with this syndrome present with an extensive and heterogeneous phenotypic spectrum. Several genes, such as EMX2 and FGFR2, were identified as the cause genital anomalies and facial dysmorphism in 10q26 deletion syndrome. However, the critical region for 10q26 deletion syndrome is not determined and the precise relationships between the causative genes and the phenotypes are still controversial. WD repeat domain 11 (WDR11), located at 10q25-26, was recently identified as a causative gene in hypogonadotropic hypogonadism, but other clinical phenotypes caused by WDR11 variants have not been identified. In this study, we have identified a WDR11 missense mutation, NM_018117.11: c.2108G > A; p.(Arg703Gln); ClinVar accession SCV000852064, in a two-year-old boy with severe growth retardation, ventricular septal defect, and coloboma symptoms. The case suggests that WDR11 is partially responsible for the clinical features of 10q26 deletion syndrome and provides novel insights into the pathophysiology of this syndrome.

A Nonsense SMAD3 Mutation in a Girl with Familial Thoracic Aortic Aneurysm and Dissection without Joint Abnormality.

INTRODUCTION: Thoracic aortic aneurysms and dissections (TAAD) are rare in children and often associated with underlying genetic disorders accompanied with other systemic manifestations, including connective or osteo-articular tissue diseases. CASE PRESENTATION: We report the case of a 10-year-old girl with a novel nonsense SMAD3 mutation, p.Glu102X, who presented with familial TAAD without any signs of osteoarthritis. Histological analysis of aorta fragments from the patient with TAAD obtained during surgery revealed elastin degradation and inflammatory infiltration of T cells with dense CD31 + microvessels, which is consistent with previous findings. Interestingly, the family members with the SMAD3 mutation developed IgA nephropathy. CONCLUSION: Because the TGF-ß/Smad signalling pathway plays an important role in the primary pathogenesis of IgA nephropathy and TAAD, we presume that IgA nephropathy could be a novel clinical phenotype of SMAD3 deficiency. Further accumulation of genetically proven cases with SMAD3 deficiency is needed to more accurately characterize phenotypic variability and elucidate a wide spectrum of TGF-ß-associated disorders.

Feasibility and Reproducibility of Fetal Left Ventricular Twist Using Two-Dimensional Speckle-Tracking Analysis in a Japanese Population.

In fetal echocardiography, conventional parameters for assessing cardiac function are limited because of limited echocardiographic windows or the fetus' position. We aimed to evaluate the feasibility and reproducibility of fetal left ventricular (LV) twist by two-dimensional, speckle-tracking echocardiography (2DSTE) in a Japanese population.We included 55 normal fetuses at gestational ages between 21 and 36 weeks. Subjects with adverse maternal health issues were excluded. LV twist was calculated as the net difference between LV basal and apical rotation at end-systole estimated with 2DSTE.We were able to analyze the 2DSTE images in 44 cases (80%). The mean (±SE) apical rotation, basal rotation, and LV twist were 7.88 ± 0.77, -3.68 ± 0.50, and 11.1 ± 0.75 degrees, respectively. We could not analyze 11 cases (20%) because of poor image quality due to fetal position in five cases (45.5%), failure to track the endocardium because of blurred images in five cases (45.5%), and failure to obtain images of the heart due to the presence of the placenta in front of the fetus in one case (9.1%). There were no significant differences in the demographic data between pregnant women in whom LV twist analysis was feasible and not feasible. The intra- and interobserver intraclass correlation coefficients were 0.67 and 0.64, respectively.LV twist analysis by 2DSTE in the fetus was feasible in a substantial population and may provide new insight into cardiac function during the prenatal period. On the other hand, its reproducibility was moderate and needs to be improved.

Detection of Pediatric Pulmonary Arterial Hypertension by School Electrocardiography Mass Screening.

Rationale: To detect pulmonary arterial hypertension (PAH) at any early stage is a promising approach to optimize the outcome. Objectives: To investigate the impact of school ECG-based screening on detecting idiopathic or heritable (I/H)-PAH in the general pediatric population. Methods: This was a nationwide survey of patients with I/H-PAH newly diagnosed at 3 months to 18 years of age in Japan during 2005-2012. Measurements and Main Results: Eighty-seven eligible patients (age range, 1-16 yr) were recruited. Among 68 (78%) patients diagnosed at greater than or equal to 6 years of age (the age of the first ECG-based screening), 28 (41%) were detected by the ECG-based screening (screening group) and 40 (59%) were recognized by their symptoms (n = 37) or coincidental occasions (n = 3; nonscreening group). In the screening group, the proportion of patients in World Health Organization functional class I/II at diagnosis was higher (96% vs. 60%; P < 0.001), plasma brain natriuretic peptide level was lower (149 ± 290 vs. 398 ± 559 pg/ml; P = 0.045), and 6-minute-walk distance was longer (420 ± 109 vs. 327 ± 104 m; P < 0.001) than the nonscreening group, despite similar values in mean pulmonary artery pressure (58 ± 17 vs. 61 ± 17 mm Hg; P = 0.42) and pulmonary vascular resistance index (18 ± 8 vs. 21 ± 11 Wood units ⋅ m2; P = 0.24) between groups. The proportion of patients on intravenous epoprostenol at the final visit was lower in the screening group than the nonscreening group (14% vs. 50; P = 0.004). Conclusions: These findings suggest that the ECG-based screening detects a unique subpopulation of pediatric patients with I/H-PAH that is associated with already established pulmonary hypertension but without obvious right heart failure and warrants investigating the prognostic significance of this system.

Atypical coronary artery aneurysms due to Kawasaki disease in Noonan syndrome with a novel PTPN11 mutation.

We report a 3-year-old boy with giant and atypical coronary artery aneurysms in the acute phase of Kawasaki disease, despite appropriate therapeutic intervention, in Noonan syndrome with a novel heterozygous PTPN11 mutation, c. 907 G>A (p.Asp303Asn). We hypothesised that this PTPN11 mutation might affect both hyperinflammation caused by Kawasaki disease and vascular fragility in the coronary artery, resulting in coronary artery aneurysms.

Elimination of Ventricular Arrhythmia in Catecholaminergic Polymorphic Ventricular Tachycardia by Targeting "Catecholamine-Sensitive Area": A Dominant-Subordinate Relationship between Origin Sites of Bidirectional Ventricular Premature Contractions.

We report on a patient diagnosed with catechoaminergic polymorphic ventricular tachycardia (CPVT) who underwent catheter ablation of ventricular premature contractions (VPCs) induced by epinephrine. VPCs were classified roughly into three types. Type 1 and Type 2 VPCs (right bundle branch block [RBBB] configuration and inferior axis) were eliminated by radiofrequency applications at the left aortic sinus of Valsalva and the anterolateral papillary muscle (APM), respectively. Although no spontaneous VPCs were seen after the elimination of Type 1 and 2 VPCs, pacing resulting in capture at the APM induced Type 3 VPC (RBBB configuration and superior axis) reproducibly. The electrophysiological findings observed in our representative case have important implications both for understanding the pathophysiology of CPVT and for considering therapeutic strategies.

Pathophysiological roles of nuclear factor kappaB (NF-kB) in pulmonary arterial hypertension: effects of synthetic selective NF-kB inhibitor IMD-0354.

AIMS: Proliferation of pulmonary arterial smooth muscle cells (PASMCs) is one histological sign of pulmonary arterial hypertension (PAH). We hypothesized that a signalling cascade from fibroblast growth factor 2 (FGF2) to plasminogen activator inhibitor 1 (PAI-1) and monocyte chemotactic protein-1 (MCP-1) via nuclear transcription factor nuclear factor kappaB (NF-kB) play a critical role in progression of PAH, and tested this hypothesis both in vivo and in vitro using a synthetic selective NF-kB inhibitor, N-(3,5-Bis-trifluoromethyl-phenyl)-5-chloro-2-hydroxy-benzamide (IMD-0354). METHODS AND RESULTS: Monocrotaline (MCT) was injected into 75 Sprague-Dawley rats. Starting at day 14 after MCT injection, we administered IMD-0354 (MCT + IMD group) or vehicle (MCT group) daily. At day 32, 65% of the MCT + IMD group were alive compared with 0% of the MCT group. IMD-0354 prevented increase of right ventricular pressure, and suppressed proliferation and induced apoptosis of PASMCs. mRNA transcript levels of FGF2, PAI-1, and tissue plasminogen activator (t-PA) were lower in MCT + IMD compared with MCT. In in vitro experiments, IMD-0354 inhibited p65 translocation to the nucleus promoted by FGF2 in PASMCs. Furthermore, the time courses of extracellular signal-regulated kinase (Erk) 1/2, MCP-1, and PAI-1 stimulated with FGF2 were each markedly shortened by IMD-0354. CONCLUSIONS: We speculate that the positive-feedback loop (Erk1/2-NF-kB-MCP-1-Erk1/2) is associated with progression of PAH by causing FGF2-induced inflammation in MCT rats. IMD-0354 has potential as a new therapeutic tool for PAH.

[Differential diagnosis of pulmonary hypertension].

Symptoms of pulmonary hypertension (PH) are very nonspecific. Therefore, the mean time from symptom onset to diagnosis is about two years. Dyspnea is the most common symptom of PH. In particular, progressive dyspnea on exertion is most frequently observed as the initial symptom and seen among almost all patients at the time of diagnosis. Physical findings are often normal in early stages. The most common sign is an accentuated pulmonic component to the second heart sound. In more advanced cases, there are signs of right heart failure such as jugular venous distension, hepatomegaly and peripheral edema. Transthoracic Doppler echocardiography is the best screening test to detect PH. Right heart catheterization is required to confirm the diagnosis of PH. However, additional examinations are performed to rule out known causes of PH.

Sibling cases of Vici syndrome: sleep abnormalities and complications of renal tubular acidosis.

Vici syndrome is a rare congenital disorder characterized by albinism, agenesis of the corpus callosum, and developmental delays. Cardiac complications usually cause poor prognosis. We report sibling cases of Vici syndrome, and address complications of renal tubular acidosis. We also demonstrate the significance of serial examinations of brain natriuretic peptides, and discuss the possible early use of a beta-blocker to control cardiomyopathy. A sleep study including polysomnography indicated functional brainstem involvement, in which muscle atonia during non-rapid sleeping eye movements, and bursts of rapid eye movements increased. These findings provide new clues for medical care of patients with Vici syndrome.