Intravenous iron infusion ameliorates anaemia and protein-losing enteropathy in patients after Fontan surgery: case series.

Protein-losing enteropathy is a severe complication of Fontan surgery and is associated with anaemia. Few studies have reported on the efficacy of an intravenous iron infusion for treating protein-losing enteropathy and low albuminemia after Fontan surgery. Herein, we present two cases of female patients who suffered from protein-losing enteropathy and low albuminemia following Fontan surgery, both of whom improved after an intravenous iron infusion.

Utility of the Angle between the Right Aortic Arch and First Branch for Detecting Double Aortic Arch via Fetal Echocardiography.

INTRODUCTION: The presence of a double aortic arch (DAA) is manifested by compressive symptoms, requiring surgery. DAA cases are classified as either complete or incomplete type. DAA and a right aortic arch with mirror image branching (mRAA) have a similar configuration to the first branch artery. The first branch of the mRAA is the left brachiocephalic artery, which appears to be the same as that of an incomplete DAA due to blood flow interruption. The present retrospective study aimed to evaluate the differences between DAA and mRAA by fetal echocardiography. METHODS: This single retrospective cohort study included all patients diagnosed with complete DAA, incomplete DAA, or mRAA at our facility between 2010 and 2022. The patients were diagnosed with complete DAA, incomplete DAA, or mRAA after birth and remaining fetal echocardiograms. The patients were divided into the DAA (complete DAA: n = 4, incomplete DAA: n = 3) and mRAA (n = 4) groups. The following three outcomes were compared: (1) angle between the right aortic arch and first branch (RF angle), (2) ratio of height to width of the region bounded by the aortic arch, first branch of the aortic arch, and descending aorta, and (3) maximum tracheal diameter on a three-vessel trachea view. RESULTS: The incomplete DAA cases were difficult to diagnose via fetal echocardiography. On fetal echocardiography, the RF angle was significantly steeper in the DAA group than in the mRAA group (median 57° [36°-69°] vs. 75° [62°-94°]; p < 0.05). The DAA and RAA groups showed no significant differences in the ratio of height to width of the region bounded by the aortic arch, first branch of the aortic arch, and descending aorta (median 0.57 [0.17-0.68] vs. 0.73 [0.56-1.0]) and maximum tracheal diameter (median 2.5 [1.4-3.3] vs. 3.2 [2.8-3.5] mm). The cut-off value for the presence of DAA was an RF angle <71°. CONCLUSION: The DAA group (complete and incomplete DAA) had a significantly steeper RF angle than the mRAA group. Therefore, RF angle measurement could improve the fetal diagnosis and postnatal prognosis of DAA.

Successful bailout stenting for critical aortic coarctation in a premature baby weighing 590 g.

Severe aortic coarctation (CoA) is a critical congenital heart disease that requires surgery as the first-line treatment in neonates. However, in very small premature infants, aortic arch repair has a relatively high mortality and morbidity rate. Bailout stenting is an alternative method that can be performed safely and effectively with low morbidity.We present a case of severe CoA in a premature baby, a monochorionic twin with selective intrauterine growth restriction. The patient was born at 31 weeks of gestation with a birth weight of 570 g. Seven days following her birth, she experienced anuria due to critical neonatal isthmic CoA. She underwent a stent implantation procedure at term neonatal, weighing 590 g. She had good dilatation of the coarcted segment with no complications. Follow-up at infancy showed no CoA recurrence. This is the world's smallest case of stenting for CoA.

Calmodulinopathy in Japanese Children　- Their Cardiac Phenotypes Are Severe and Show Early Onset in Fetal Life and Infancy.

BACKGROUND: Cardiac calmodulinopathy, characterized by a life-threatening arrhythmia and sudden death in the young, is extremely rare and caused by genes encoding calmodulin, namely calmodulin 1 (CALM1), CALM2, and CALM3.Methods and Results: We screened 195 symptomatic children (age 0-12 years) who were suspected of inherited arrhythmias for 48 candidate genes, using a next-generation sequencer. Ten probands were identified as carrying variants in any of CALM1-3 (5%; median age 5 years), who were initially diagnosed with long QT syndrome (LQTS; n=5), catecholaminergic polymorphic ventricular tachycardia (CPVT; n=3), and overlap syndrome (n=2). Two probands harbored a CALM1 variant and 8 probands harbored 6 CALM2 variants. There were 4 clinical phenotypes: (1) documented lethal arrhythmic events (LAEs): 4 carriers of N98S in CALM1 or CALM2; (2) suspected LAEs: CALM2 p.D96G and D132G carriers experienced syncope and transient cardiopulmonary arrest under emotional stimulation; (3) critical cardiac complication: CALM2 p.D96V and p.E141K carriers showed severe cardiac dysfunction with QTc prolongation; and (4) neurological and developmental disorders: 2 carriers of CALM2 p.E46K showed cardiac phenotypes of CPVT. Beta-blocker therapy was effective in all cases except cardiac dysfunction, especially in combination with flecainide (CPVT-like phenotype) and mexiletine (LQTS-like). CONCLUSIONS: Calmodulinopathy patients presented severe cardiac features, and their onset of LAEs was earlier in life, requiring diagnosis and treatment at the earliest age possible.

Novel Calmodulin Variant p.E46K Associated With Severe Catecholaminergic Polymorphic Ventricular Tachycardia Produces Robust Arrhythmogenicity in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes.

BACKGROUND: CaM (calmodulin) is a ubiquitously expressed, multifunctional Ca2+ sensor protein that regulates numerous proteins. Recently, CaM missense variants have been identified in patients with malignant inherited arrhythmias, such as long QT syndrome and catecholaminergic polymorphic ventricular tachycardia (CPVT). However, the exact mechanism of CaM-related CPVT in human cardiomyocytes remains unclear. In this study, we sought to investigate the arrhythmogenic mechanism of CPVT caused by a novel variant using human induced pluripotent stem cell (iPSC) models and biochemical assays. METHODS: We generated iPSCs from a patient with CPVT bearing CALM2 p.E46K. As comparisons, we used 2 control lines including an isogenic line, and another iPSC line from a patient with long QT syndrome bearing CALM2 p.N98S (also reported in CPVT). Electrophysiological properties were investigated using iPSC-cardiomyocytes. We further examined the RyR2 (ryanodine receptor 2) and Ca2+ affinities of CaM using recombinant proteins. RESULTS: We identified a novel de novo heterozygous variant, CALM2 p.E46K, in 2 unrelated patients with CPVT accompanied by neurodevelopmental disorders. The E46K-cardiomyocytes exhibited more frequent abnormal electrical excitations and Ca2+ waves than the other lines in association with increased Ca2+ leakage from the sarcoplasmic reticulum via RyR2. Furthermore, the [3H]ryanodine binding assay revealed that E46K-CaM facilitated RyR2 function especially by activating at low [Ca2+] levels. The real-time CaM-RyR2 binding analysis demonstrated that E46K-CaM had a 10-fold increased RyR2 binding affinity compared with wild-type CaM which may account for the dominant effect of the mutant CaM. Additionally, the E46K-CaM did not affect CaM-Ca2+ binding or L-type calcium channel function. Finally, antiarrhythmic agents, nadolol and flecainide, suppressed abnormal Ca2+ waves in E46K-cardiomyocytes. CONCLUSIONS: We, for the first time, established a CaM-related CPVT iPSC-CM model which recapitulated severe arrhythmogenic features resulting from E46K-CaM dominantly binding and facilitating RyR2. In addition, the findings in iPSC-based drug testing will contribute to precision medicine.

Utility of novel echocardiographic measurements to improve prenatal diagnosis of coarctation of the aorta.

Prenatal recognition of coarctation of the aorta (CoA) may improve neonatal survival and reduce morbidity. However, prenatal diagnosis of CoA remains challenging, with relatively high false-positive and false-negative rates. This study aimed to identify a novel formula based on fetal echocardiographic measures to predict prenatal identification of CoA. A retrospective comparison on the echocardiographic evaluation of 30 patients with suspected CoA between May 2016 and April 2021 was performed. The patients were divided into a postnatal surgical intervention group (n = 13) and a non-intervention group (n = 17). The measurements that showed significant differences were aortic isthmus diameter Z-score (p < 0.001), ductus arteriosus diameter/aortic isthmus diameter (p < 0.001), and distal aortic arch (DA) index (p < 0.001). In the receiver operating characteristic curves analysis, the DA index was the largest with an area under the curve of 0.941 and a cutoff value of 1.28, with a sensitivity of 85% and a specificity of 94%. Measurement of the DA index improved the diagnostic rate of fetal CoA and a DA index ≧ 1.28 indicated fetal CoA cases requiring surgical intervention.

Control of Heart Rate in Infant and Child Tachyarrhythmia With Reduced Cardiac Function Using Landiolol (HEARTFUL)　- Results of a Prospective, Multicenter, Uncontrolled Clinical Study.

BACKGROUND: The prospective Control of HEART rate in inFant and child tachyarrhythmia with reduced cardiac function Using Landiolol (HEARTFUL) study investigated the effectiveness and safety of landiolol, a short-acting ß1 selective blocker, in children.Methods and Results: Twenty-five inpatients aged ≥3 months to <15 years who developed supraventricular tachyarrhythmias (atrial fibrillation, atrial flutter, supraventricular tachycardia, and inappropriate sinus tachycardia) were treated with landiolol. The primary endpoint, the percent of patients with a reduction in heart rate ≥20% from the initial rate of tachycardia, or termination of tachycardia at 2 h after starting landiolol, was achieved in 12/25 patients (48.0%; 95% CI 28.4-67.6), which exceeded the predetermined threshold (38.0%). At 2 h after starting landiolol administration, heart rate had decreased by ≥20% in 45.8% (11/24) and recovery to sinus rhythm was achieved in 40.0% (6/15) of the patients. Adverse reactions (ARs) occurred in 24.0% (6/25) of patients, and the study was discontinued in 4.0% (1/25) of the patients; however, none of these ARs were considered serious. The most common AR was hypotension (20.0% [5/25] of patients). CONCLUSIONS: The HEARTFUL study has demonstrated the efficacy of landiolol, by reducing heart rate or terminating tachycardia, in pediatric patients with supraventricular tachyarrhythmias. Although serious ARs and concerns were not identified in this study, physicians should be always cautious of circulatory collapse due to hypotension.

Transconduit approach for pulmonary vein stenting in an extracardiac Fontan and plastic bronchitis case.

Plastic bronchitis (PB) is a rare but severe complication in patients following the Fontan operation, the final palliative procedure for single ventricle heart disease. PB is characterised by the formation of rubbery casts of the tracheobronchial tree that may cause cough, wheezing, dyspnoea and hypoxia. Progressive airway obstruction may lead to asphyxia and death, and the overall mortality rate is 15.2%. Most patients receive a combination therapy from three different treatment strategies, that is, therapy for relief of airway obstruction, anti-inflammatory treatment and treatment to improve haemodynamics of the Fontan physiology. Therapy improving haemodynamics consists of optimising the Fontan circulation or cardiac function, antiarrhythmic therapy, inhibition of lymph leakage/production, decompression of the Fontan circulation and heart transplantation.We present the case of a child with PB after extracardiac Fontan operation, who was refractory to balloon angioplasty and surgical release for pulmonary vein (PV) stenosis. We decided to perform stent implantation for the right PVs through transconduit puncture instead of fenestration because the position of fenestration was too high to access the PVs. After PV stenting via the transconduit approach, she experienced improvement in cough, wheezing and breathlessness, and a significant reduction in airway cast formation.

Asymptomatic latent Wolff-Parkinson-White syndrome detected during school heart screening: a case Report.

In latent Wolff-Parkinson-White syndrome, ventricular pre-excitation is inapparent during sinus rhythm but carries the same possibility of sudden cardiac death and palpitations as overt Wolff-Parkinson-White syndrome. It is difficult to diagnose latent Wolff-Parkinson-White syndrome when a patient does not have syncope or palpitations. We report the case of an asymptomatic patient with latent Wolff-Parkinson-White syndrome detected on school heart screening using subtle electrocardiography findings.

Association Between Deleterious SCN5A Variants and Ventricular Septal Defect in Young Patients With Brugada Syndrome.

OBJECTIVES: This study aimed to investigate the clinical characteristics of young patients with Brugada syndrome (BrS) with ventricular septal defect (VSD) and explore their genetic backgrounds. BACKGROUND: VSD is the most frequently occurring congenital heart disease among children. In contrast, BrS is a rare hereditary disease that is responsible for ventricular fibrillation and sudden cardiac death. Owing to their low incidence, the genetic background and clinical characteristics of patients with BrS with VSD have not been elucidated yet. METHODS: This study enrolled 36 individuals who were diagnosed with BrS when they were <20 years of age and performed genetic screening for SCN5A. The functional alteration in mutant Na+ channels was confirmed by patch clamp technique. RESULTS: Among the 36 patients with BrS, 5 had been diagnosed with VSD. This study found 14 heterozygous SCN5A variants in 15 unrelated patients. The 5 patients with VSD carried SCN5A variants, including R367S, R535∗, R893C, W1345C, and G1743R. The 3 missense variants (R893C, W1345C, and G1743R) have been proved to reduce peak Na+ current to <10%. A functional analysis of SCN5A R367S was performed and the variant was found to be nonfunctional. CONCLUSIONS: This study identified 5 loss-of-function SCN5A variants in 5 young patients with BrS with VSD. The study hypothesizes that altered blood flow in the right ventricular outflow tract leads to fibrosis and electrophysiological changes, predisposing the patients to earlier clinical presentation of BrS. In patients with VSD and ST-segment elevation in the right precordial leads, BrS should be considered and appropriate screening should be pursued accordingly.

School-based routine screenings of electrocardiograms for the diagnosis of long QT syndrome.

AIMS: School-based routine screenings of electrocardiograms (ECGs) have been performed upon admission to primary school (PS), junior high school (JHS), and high school (HS) in Japan. Though ECGs with prolonged QT intervals are occasionally found, the role of regular ECG screening tests in identifying long QT syndrome (LQTS) remains to be determined. We investigated the usefulness of the ECG screenings by comparing the results of genetic tests between students who showed QT-prolongation in the screenings and patients with LQTS. METHODS AND RESULTS: We genetically screened 341 students (106 PS, 173 JHS, and 62 HS). Of these, 230 subjects showed QT-prolongation during regular screenings (S-S group), and the other 111 patients were clinically consulted with suspected LQTS by paediatricians (C-C group). Genotype-phenotype relationships were compared between the two groups. The positive rates in the genetic tests were comparable among the two groups; however, symptomatic subjects were significantly fewer in the S-S group than the C-C group (3% vs. 70%). Compared to the genotype-negative subjects, the positive subjects showed significantly longer QTc (P < 0.0001) and more frequently presented LQTS risk scores with ≥3.5 points (P < 0.0001). Lethal arrhythmic events (LAE) occurred only in the C-C group; 18 subjects experienced LAE and 83% of them were found to carry variant(s) in the LQTS-related genes. CONCLUSION: The school-based ECG screenings are effective in identifying young patients with LQTS who require genetic analysis. If individuals are screened at a younger age, we can identify patients at risk earlier and provide preventative treatments.

Loss-of-function mutations in cardiac ryanodine receptor channel cause various types of arrhythmias including long QT syndrome.

AIMS: Gain-of-function mutations in RYR2, encoding the cardiac ryanodine receptor channel (RyR2), cause catecholaminergic polymorphic ventricular tachycardia (CPVT). Whereas, genotype-phenotype correlations of loss-of-function mutations remains unknown, due to a small number of analysed mutations. In this study, we aimed to investigate their genotype-phenotype correlations in patients with loss-of-function RYR2 mutations. METHODS AND RESULTS: We performed targeted gene sequencing for 710 probands younger than 16-year-old with inherited primary arrhythmia syndromes (IPAS). RYR2 mutations were identified in 63 probands, and 3 probands displayed clinical features different from CPVT. A proband with p.E4146D developed ventricular fibrillation (VF) and QT prolongation whereas that with p.S4168P showed QT prolongation and bradycardia. Another proband with p.S4938F showed short-coupled variant of torsade de pointes (scTdP). To evaluate the functional alterations in these three mutant RyR2s and p.K4594Q previously reported in a long QT syndrome (LQTS), we measured Ca2+ signals in HEK293 cells and HL-1 cardiomyocytes as well as Ca2+-dependent [3H]ryanodine binding. All mutant RyR2s demonstrated a reduced Ca2+ release, an increased endoplasmic reticulum Ca2+, and a reduced [3H]ryanodine binding, indicating loss-of-functions. In HL-1 cells, the exogenous expression of S4168P and K4594Q reduced amplitude of Ca2+ transients without inducing Ca2+ waves, whereas that of E4146D and S4938F evoked frequent localized Ca2+ waves. CONCLUSION: Loss-of-function RYR2 mutations may be implicated in various types of arrhythmias including LQTS, VF, and scTdP, depending on alteration of the channel activity. Search of RYR2 mutations in IPAS patients clinically different from CPVT will be a useful strategy to effectively discover loss-of-function RYR2 mutations.

Catheter ablation in children and patients with congenital heart disease: Review of 1021 procedures at a high-volume single center in Japan.

BACKGROUND: Although pediatric catheter ablation therapy has often been described, few reports on outcomes in a large series of patients at a single center are available. OBJECTIVE: The purpose of this study was to evaluate arrhythmia substrates, outcomes, and complications of catheter ablation in children and patients with congenital heart disease (CHD) performed at a single center. METHODS: We retrospectively analyzed all pediatric patients <18 years and patients of all ages with CHD who underwent ablation therapy between June 2006 and May 2018. RESULTS: A total of 1021 ablation procedures were performed in 877 patients (median age 12.5 years; range 2 months to 67 years). This cohort included 152 CHD patients, 90 small patients (<15 kg), and 14 infants (<1 year). The most frequent indication was Wolff-Parkinson-White pattern (WPW) (n = 287 [32.7%]). Of the 55 patients with asymptomatic WPW, 40 patients (72.7%) had retrograde accessory pathway conduction. Overall success and recurrence rates were 93.5% and 17.3%, respectively. Small patients and CHD patients had lower success rates. No deaths occurred. Serious complications occurred in 5 patients. CONCLUSION: Catheter ablation is safe and effective for treatment of arrhythmia in pediatric and CHD patients. However, ablation was less successful in small patients and CHD patients. The risk of complications was similar to those previously reported for catheter ablation in pediatric, CHD, and adult patients.

Successful catheter ablation of premature ventricular contractions triggering torsade de pointes in a small infant with histiocytoid cardiomyopathy: a case report.

BACKGROUND: A short-coupled variant of torsade de pointes (ScTdP) is rare and resistant to medical treatment. There has not been a reported catheter ablation (CA) of a short-coupled premature ventricular contraction (PVC) triggering ScTdP in an infant. CASE SUMMARY: A neonate was referred to our hospital on the day of birth for Wolff-Parkinson-White syndrome, repeated episodes of supraventricular tachycardia, and a left ventricular non-compaction. She underwent CA of an accessory pathway at 72 days of age. On the 5th day after ablation, she had recurrent TdP episodes resistant to various antiarrhythmic drugs and received extracorporeal membrane oxygenation at 86 days of age. She underwent CA of PVCs triggering TdP at 122 days of age and a weight of 3.4 kg. Two types of PVCs triggering TdP were successfully ablated, which originated from the right ventricle (RV). Pre-potentials were recorded at the earliest ventricular activation sites of the targeted PVCs. After the ablation, she had no TdP episodes and the cardiac assist device was removed. However, she died of uncontrolled heart failure at 6 months of age. The histological findings were compatible with histiocytoid cardiomyopathy and abnormal cells were distributed throughout both ventricles. At the ablation site, fibrotic transmural lesions were noted in the RV wall. DISCUSSION: The PVCs triggering TdP were successfully ablated in a 4-month-old girl with histiocytoid cardiomyopathy. The PVCs were likely caused by triggered activity and associated with abnormal Purkinje cells.

Post-Extubation Inhaled Nitric Oxide Therapy via High-Flow Nasal Cannula After Fontan Procedure.

In 2014, our hospital introduced inhaled nitric oxide (iNO) therapy combined with high-flow nasal cannula (HFNC) oxygen therapy after extubation following the Fontan procedure in patients with unstable hemodynamics. We report the benefits of HFNC-iNO therapy in these patients. This was a single-center, retrospective review of 38 patients who underwent the Fontan procedure between January 2010 and June 2016, and required iNO therapy before extubation. The patients were divided into two groups: patients in Epoch 1 (n = 24) were treated between January 2010 and December 2013, receiving only iNO therapy; patients in Epoch 2 (n = 14) were treated between January 2014 and June 2016, receiving iNO therapy and additional HFNC-iNO therapy after extubation. There were no significant differences between Epoch 1 and 2 regarding preoperative cardiac function, age at surgery, body weight, initial diagnosis (hypoplastic left heart syndrome, 4 vs. 2; total anomalous pulmonary venous return, 5 vs. 4; heterotaxy, 7 vs. 8), intraoperative fluid balance, or central venous pressure upon admission to the intensive care unit. Epoch 2 had a significantly shorter duration of postoperative intubation [7.2 (3.7-49) vs. 3.5 (3.0-4.6) hours, p = 0.033], pleural drainage [23 (13-34) vs. 9.5 (8.3-18) days, p = 0.007], and postoperative hospitalization [36 (29-49) vs. 27 (22-36) days, p = 0.017]. Two patients in Epoch 1 (8.3%), but none in Epoch 2, required re-intubation. Our results suggest that HFNC-iNO therapy reduces the duration of postoperative intubation, pleural drainage, and hospitalization.

The closing process of the ductus arteriosus connecting the left common carotid artery and main pulmonary artery.

An isolated left common carotid artery is very rare, and only 13 cases have been reported thus far. All those cases were accompanied by a right aortic arch and aberrant left subclavian artery, and the connecting vessel between the pulmonary artery and left common carotid artery was thought to be ductal tissue. However, there have been no reports that have followed the natural closure of this vessel. We present a case in whom we could observe the closing process of this vessel at the connection between the left common carotid artery and main pulmonary artery in association with a tetralogy of Fallot.

Left ventricular function after a Fontan operation in patients with pulmonary atresia with an intact ventricular septum.

OBJECTIVES: In patients with pulmonary atresia with an intact ventricular septum (PA/IVS), there are no reports about the impact of sinusoidal communication (SC) on left ventricular (LV) performance after a Fontan operation; therefore, the purpose of this study was to fill this gap in the literature. METHODS: We performed a single-centre, retrospective study of 46 patients with PA/IVS. Nineteen patients who underwent the Fontan procedure were enrolled and divided into 2 groups: those with SC (SC group) and those without SC (N group). The 2 groups were compared in terms of postoperative cardiac function. RESULTS: Thirteen patients were in the SC group (4 patients with right ventricle-dependent coronary circulation) and 6, in the N group. Although 2 of the patients with right ventricular (RV)-dependent coronary circulation showed focal asynergy of the LV wall, others showed no findings of myocardial infarction. The patients' preoperative age and age during the observation period after the Fontan operation did not differ. There was no difference in LV ejection fraction, cardiac index and RV and pulmonary artery pressure before and after the Fontan operation. Preoperative RV volume in the N group was greater than that in the SC group. Brain natriuretic peptide levels were higher in the SC group after the Fontan operation. On ventricular efficacy analysis, contractility was lower (1.8 ± 0.32 vs 2.5 ± 0.40 mmHg/ml/m2, P = 0.001) and ventricular efficacy was worse (1.0 ± 0.15 vs 0.86 ± 0.11, P = 0.046) in the SC group during the postoperative period. CONCLUSIONS: Compared to patients with PA/IVS without SC, patients with PA/IVS with SC had a low cardiac contractility and decreased cardiac output efficiency after the Fontan procedure.

Electrical disorders in atrial septal defect: genetics and heritability.

Atrial septal defect (ASD) is one of the most common types of congenital heart diseases (CHDs). Most ASDs occur sporadically, but some are inherited and associated with cardiac conduction defects such as atrioventricular block (AVB) or bundle branch block. Mutations in genes encoding transcription factor gene TBX5 and NKX2-5, were found in Holt-Oram syndrome (HOS) and ASD with atrioventricular (AV) conduction defects, respectively. HOS is characterized by upper limb anomaly in addition to ASD and AVB (heart-hand syndrome). ASD associated with NKX2-5 is rare but is reported to cause sudden cardiac death (SCD) or cardiomyopathy. We provide a review of these two diseases.