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Atrial flutter (AFL) in pediatric patients is a rare condition as the physical dimensions of the immature heart are inadequate to support the arrhythmia. This low incidence makes it difficult for patients in this particular setting to be studied. AFL accounts for 30% of fetal tachyarrhythmias, 11% to 18% of neonatal tachyarrhythmias, and 8% of supraventricular tachyarrhythmias in children older than 1 year of age. Transesophageal overdrive pacing can be used, instead, with lower success rate (60%-70%). The recommended drugs are digoxin which can decrease the ventricular rate until the spontaneous interruption of the AFL. Digoxin can be combined with flecainide or amiodarone in case of failure.

Aims Subcutaneous-implantable cardiac defibrillators (S-ICDs) are used increasingly to prevent sudden cardiac death in young patients. This study was set up to gain insight in the indications for S-ICD, possible complications, and their predictors and follow-up results. Methods and results A multicentre, observational, retrospective, non-randomized, standard-of-care registry on S-ICD outcome in young patients with congenital heart diseases (CHDs), inherited arrhythmias (IAs), idiopathic ventricular fibrillation (IVF), and cardiomyopathies (CMPs). Anthropometry was registered as well as implantation technique, mid-term device-related complications, and incidence of appropriate/inappropriate shocks (IASs). Data are reported as median (interquartile range) or mean ± standard deviation. Eighty-one patients (47% CMPs, 20% CHD, 21% IVF, and 12% IA), aged 15 (14–17) years, with body mass index (BMI) 21.8 ± 3.8 kg/m2, underwent S-ICD implantation (primary prevention in 59%). This was performed with two-incision technique in 81% and with a subcutaneous pocket in 59%. Shock and conditional zones were programmed at 250 (200–250) and 210 (180–240) b.p.m., respectively. No intraoperative complications occurred. Follow up was 19 (6–35) months: no defibrillation failure occurred, 17% of patients received appropriate shocks, 13% of patients received IAS (supraventricular tachycardias 40%, T-wave oversensing 40%, and non-cardiac oversensing 20%). Reprogramming, proper drug therapy, and surgical revision avoided further IAS. Complications requiring surgical revision occurred in 9% of patients, with higher risks in patients with three-incision procedures [hazard ratio (HR) 4.3, 95% confidence interval (95% CI) 0.5–34, P = 0.038] and BMI < 20 (HR 5.1, 95% CI 1–24, P = 0.031). Conclusion This multicentre European paediatric registry showed good S-ICD efficacy and safety in young patients. Newer implantation techniques and BMI > 20 showed better outcome.

Despite the decades-old knowledge that males and people with diabetes mellitus (DM) are at increased risk for coronary artery disease (CAD), the reasons for this association are only partially understood. Among the immune cells involved, recent evidence supports a critical role of T cells as drivers and modifiers of CAD. CD4+ T cells are commonly found in atherosclerotic plaques. We aimed to understand the relationship of CAD with sex and DM by single-cell RNA (scRNA-Seq) and antibody sequencing (CITE-Seq) of CD4+ T cells. Peripheral blood mononuclear cells (PBMCs) of 61 men and women who underwent cardiac catheterization were interrogated by scRNA-Seq combined with 49 surface markers (CITE-Seq). CAD severity was quantified using Gensini scores, with scores above 30 considered CAD+ and below 6 considered CAD−. Four pairs of groups were matched for clinical and demographic parameters. To test how sex and DM changed cell proportions and gene expression, we compared matched groups of men and women, as well as diabetic and non-diabetic subjects. We analyzed 41,782 single CD4+ T cell transcriptomes for sex differences in 16 women and 45 men with and without coronary artery disease and with and without DM. We identified 16 clusters in CD4+ T cells. The proportion of cells in CD4+ effector memory cluster 8 (CD4T8, CCR2+ Em) was significantly decreased in CAD+, especially among DM+ participants. This same cluster, CD4T8, was significantly decreased in female participants, along with two other CD4+ T cell clusters. In CD4+ T cells, 31 genes showed significant and coordinated upregulation in both CAD and DM. The DM gene signature was partially additive to the CAD gene signature. We conclude that (1) CAD and DM are clearly reflected in PBMC transcriptomes, and (2) significant differences exist between women and men and (3) between subjects with DM and non-DM.

The adaptive immune response plays an important role in atherosclerosis. In response to a high fat/high cholesterol diet, marginal zone B (MZB) cells activate an atheroprotective programme by regulating the differentiation and accumulation of T follicular helper (Tfh) cells. On the other hand, Tfh cells activate the germinal centre response, which promotes atherosclerosis in part through the production of class-switched high-affinity antibodies. However, the direct role of Tfh cells in atherosclerosis remains poorly understood. Here, using a low-density lipoprotein receptor deficient (Ldlr-/-) atherogenic mouse model with selective genetic deletion of Tfh cells, we unexpectedly found that Tfh protect from early atherosclerosis. Mice lacking Tfh had decreased class-switched IgG antibodies against oxidation-specific epitopes (OSE), but also decreased atheroprotective natural IgM-type anti-phosphorycholine (PC) antibodies, despite no alteration of natural B1 cells. RNAseq of MZB cells showed that these cells failed to activate their antibody-secreting machinery in the absence of Tfh. Moreover, MZB cell deficiency in Ldlr-/- mice was associated with a significant decrease in atheroprotective IgM antibodies, including natural anti-PC IgM. In humans, we find a positive correlation between circulating MZB-like cells and anti-OSE IgM antibodies. Finally, we identify an important role for IL18 signalling in high fat/high cholesterol diet-induced Tfh. Our findings reveal a previously unsuspected role of MZB cells in regulating atheroprotective “natural” IgM antibody production in a Tfh-dependent manner, which could have important pathophysiological and therapeutic implications.

Background: Detailed understanding of the immune response to severe acute respiratory syndrome coronavirus (SARS-CoV)-2, the cause of coronavirus disease 2019 (CO­VID-19) has been hampered by a lack of quantitative antibody assays. Objective: The objective was to develop a quantitative assay for IgG to SARS-CoV-2 proteins that could be implemented in clinical and research laboratories. Methods: The biotin-streptavidin technique was used to conjugate SARS-CoV-2 spike receptor-binding domain (RBD) or nucleocapsid protein to the solid phase of the ImmunoCAP. Plasma and serum samples from patients hospitalized with COVID-19 (n = 60) and samples from donors banked before the emergence of COVID-19 (n = 109) were used in the assay. SARS-CoV-2 IgG levels were followed longitudinally in a subset of samples and were related to total IgG and IgG to reference antigens using an ImmunoCAP 250 platform. Results: At a cutoff of 2.5 μg/mL, the assay demonstrated sensitivity and specificity exceeding 95% for IgG to both SARS-CoV-2 proteins. Among 36 patients evaluated in a post-hospital follow-up clinic, median levels of IgG to spike-RBD and nucleocapsid were 34.7 μg/mL (IQR 18–52) and 24.5 μg/mL (IQR 9–59), respectively. Among 17 patients with longitudinal samples, there was a wide variation in the magnitude of IgG responses, but generally the response to spike-RBD and to nucleocapsid occurred in parallel, with peak levels approaching 100 μg/mL, or 1% of total IgG. Conclusions: We have described a quantitative assay to measure IgG to SARS-CoV-2 that could be used in clinical and research laboratories and implemented at scale. The assay can easily be adapted to measure IgG to mutated COVID-19 proteins, has good performance characteristics, and has a readout in standardized units.

Aims The aims of this study are to evaluate the progressive involvement of the cardiac conduction system in the Kearn–Sayre syndrome (KSS) and to establish criteria for the prevention of episodes of syncope or sudden cardiac death. Methods and results This is a prospective monocentric study including KSS patients, with diagnosis based on clinical manifestations, muscle biopsy, and genetic tests, before the age of 18. All patients underwent cardiac screening examination with 12-lead electrocardiogram (ECG), 24-h Holter monitoring, and pacemaker (PM) interrogation twice a year. Fifteen patients (nine males, mean age 16.6 ± 3.9 years) with a sporadic KSS were recruited. All subjects manifested at least one of the intraventricular conduction defects (IVDs): 1 right bundle branch block (RBBB), 2 left anterior fascicular block (LAFB), 11 a bi-fascicular block (RBBB + LAFB), and 1 left posterior fascicular block. Most children with bi-fascicular block developed LAFB before the RBBB (P = 0.0049). In six patients, IVD degenerated into atrioventricular block (AVB). Endocavitary PM was implanted in 11 patients (6 with AVB and 5 with a bi-fascicular block), while an implantable cardioverter-defibrillator only in one patient with a non-sustained ventricular tachycardia. Four died at mean age of 14.7 ± 2.6 years, but none of them suddenly. Conclusion Even a ‘simple’ ECG can predict the arrhythmic risk and the occurrence of catastrophic events in young patients with KSS. Left anterior fascicular block precedes RBBB in determining the bi-fascicular block and this can predict an inexorable progression of the conduction defects even in a short time. Pacemaker implantation may be indicated in these patients since the first bi-fascicular block manifestation.

OBJECTIVES We sought to evaluate the long-term survival and risk factors for morbidity and mortality in our cohort of patients after extracardiac (EC) Fontan. METHODS We collected and analysed follow-up data until September 2020 for all patients who underwent EC Fontan operation at our institution from November 1988 to November 2015. RESULTS Out of 406 patients treated with EC Fontan at a mean age of 5.4 ± 4.5 years, 372 (91.6%) were discharged home; 15% were lost to follow-up. The median follow-up was 14.6 years (interquartile range 8.7–20.3). Two hundred patients (54%) had a good long-term outcome, with an event-free long-term survival, but late adverse events of any kind needing interventional or surgical reoperations were reported in 128 patients (34%). Forty-four patients (12%) developed late Fontan failure. Thirty-seven survivors (10%) had late arrhythmias, with the need for pacemaker implantation. Obstruction of the cavopulmonary pathway occurred in 49 patients (13%), but just 8 patients needed conduit surgical replacement. At 32 years, the survival probability was 84%. The risk of orthotopic heart transplant, considering death as a competing event (showed as cumulative incidence), was 12.5%. A preoperative diagnosis of hypoplastic left heart syndrome was an independent risk factor for the need for heart transplant. CONCLUSIONS The EC Fontan shows satisfactory long-term survival and low incidence of adverse events and late failure. Conduit replacement is rare, and its longevity may not represent a substantial issue in these patients. However, as with other technical variants, the need for reoperations during long-term follow-up is a significant challenge.

Optimal treatment adherence is critical in the management of breast cancer patients/survivors taking hormonal therapy. However, lack of adherence is common. Many technologies have been developed to encourage medication intake, such as reminders on phones or digital pills, with varying degrees of success.To explore the role of technology in medical adherence requires a framework that considers all complexities of technology, from software to the end user's beliefs. Actor Network Theory (ANT) defines technology based on its technical, social, and abstract components. We conducted three focus groups, which we analyzed using a thematic analysis to determine topics in breast cancer survivors' discussions of these technologies. We also conducted a deductive content analysis using ANT concepts as codes.In discussing the use of technology to improve medical adherence, participants had an empowering view of technology (48.8%) a neutral one (41.5%) or a disempowering view (9.8%). When it comes to their medication adherence, breast cancer survivors taking hormonal therapy perceived technology as something on which they could assert agency while their own agency dictated their adherence behaviors.In line with a non-technologically deterministic view of medical technologies, this finding shows that technology can be both constraining and enabling, depending on the specific context of human use. This networked understanding of technology in terms of social dynamics has relevant implications in designing interventions that use technology to improve adherence.

Recent work by our group and others have shown individuals with IgE to the oligosaccharide allergen present in mammalian products (α-gal) have increased atheroma burden with increased necrosis and calcification compared to those without α -gal specific IgE. These data suggest α -gal specific IgE increase plaque severity and vulnerability, yet the mechanisms that promote production of IgE to α -gal are unknown. Previous work from our group utilized multi-omics single cell analysis of circulating PBMCs from subjects with coronary angiography at UVA and showed subjects with IgE α -gal sensitization had a higher frequency of CCR6hi switched memory (SWM) B cells and that the CCR6 ligand, CCL20, increased class switching to IgE. To determine mechanisms whereby CCR6 may mediated class switching to IgE, we enriched total B cells from healthy donor peripheral blood mononuclear cells and stimulated with 20ng/ml human IL-4 and 10μg/ml agnostic anti-human CD40 with or without 20ng/ml CCL20 for 3 days. After 3 days of treatment, cells were collected and stained with a 15-color panel and analyzed via flow cytometry. Cells were analyzed for surface expression of CD20 and CD3 to gate total B cells. Gated B cells were further separated into CD27+/IgM-/IgD- to define SWM B cell population. CCL20 treatment did not increase the total percent of SWM B cells; however, there was a 2-3-fold increase in CCR6+ SWM B cells compared to CCR6- SWM B cells. CCL20 treated CCR6+ SWM B cells have an average of 7% increase of phosphorylated mTOR in total SWM B cells compared to nonCCL20 treated CCR6+ SWM B cells. These results suggest CCL20 stimulation induces mTOR phosphorylation and activation. Thus, mTOR activation and downstream mediators may be necessary for α -gal induced B cell class switching. From these preliminary studies, we conclude that CCL20 stimulation increases the percent pmTOR+ SWM B cells. We will continue to investigate downstream mTOR mediators in regard to B cell class switching after CCL20 stimulation and how α-gal sensitization augments B cell IgE class switching and increases atherosclerosis with our novel α -gal-/- Apoe-/- mouse.

We report a unique case of a 6-year-old male child with aborted sudden cardiac death due to ventricular fibrillation. A rare anomalous aortic origin of the right coronary artery was detected and supposed to be the cause of the malignant arrhythmia. Clinical exome sequencing did not reveal any pathogenic variant related to channelopathies nor other known heart-related genes. The patient underwent cardiac surgery and a cardiac defibrillator was implanted for secondary prevention.

Aims In the current literature, results of the low-voltage bridge (LVB) ablation strategy for the definitive treatment of atrioventricular nodal re-entry tachycardia (AVNRT) seem to be encouraging also in children. The aims of this study were (i) to prospectively evaluate the mid-term efficacy of LVB ablation in a very large cohort of children with AVNRT, and (ii) to identify electrophysiological factors associated with recurrence. Methods and results One hundred and eighty-four children (42% male, mean age 13 ± 4 years) with AVNRT underwent transcatheter cryoablation guided by voltage mapping of the Koch’s triangle. Acute procedural success was 99.2% in children showing AVNRT inducibility at the electrophysiological study. The overall recurrence rate was 2.7%. The presence of two LVBs, a longer fluoroscopy time and the presence of both typical and atypical AVNRT, were found to be significantly associated with an increased recurrence rate during mid-term follow-up. Conversely, there was no significant association between recurrences and patient’s age, type of LVB, lesion length, number of cryolesions or catheter tip size. Conclusion The LVB ablation strategy is very effective in AVNRT treatment in children. Recurrences are related to the complexity of the arrhythmogenic substrate.

Although cardiovascular magnetic resonance (CMR) imaging measurements are known to differ between sexes and according to age in the normal heart, little is known about measurement variability in patients with congenital heart disease (CHD). Yet, aggregate CMR data, without adjustment for sex or age

Background: Symptomatic children with catecholaminergic polymorphic ventricular tachycardia (CPVT) are at risk for recurrent arrhythmic events. β-Blockers decrease this risk, but studies comparing individual β-blockers in sizeable cohorts are lacking. We aimed to assess the association between risk for arrhythmic events and type of β-blocker in a large cohort of symptomatic children with CPVT. Methods: From 2 international registries of patients with CPVT, RYR2 variant–carrying symptomatic children (defined as syncope or sudden cardiac arrest before β-blocker initiation and age at start of β-blocker therapy Results: We included 329 patients (median age at diagnosis, 12 [interquartile range, 7–15] years, 35% females). Ninety-nine (30.1%) patients experienced the primary outcome and 74 (22.5%) experienced the secondary outcome during a median follow-up of 6.7 (interquartile range, 2.8–12.5) years. Two-hundred sixteen patients (66.0%) used a nonselective β-blocker (predominantly nadolol [n=140] or propranolol [n=70]) and 111 (33.7%) used a β1-selective β-blocker (predominantly atenolol [n=51], metoprolol [n=33], or bisoprolol [n=19]) as initial β-blocker. Baseline characteristics did not differ. The HRs for both the primary and secondary outcomes were higher for β1-selective compared with nonselective β-blockers (HR, 2.04 [95% CI, 1.31–3.17]; and HR, 1.99 [95% CI, 1.20–3.30], respectively). When assessed separately, the HR for the primary outcome was higher for atenolol (HR, 2.68 [95% CI, 1.44–4.99]), bisoprolol (HR, 3.24 [95% CI, 1.47–7.18]), and metoprolol (HR, 2.18 [95% CI, 1.08–4.40]) compared with nadolol, but did not differ from propranolol. The HR of the secondary outcome was only higher in atenolol compared with nadolol (HR, 2.68 [95% CI, 1.30–5.55]). Conclusions: β1-selective β-blockers were associated with a significantly higher risk for arrhythmic events in symptomatic children with CPVT compared with nonselective β-blockers, specifically nadolol. Nadolol, or propranolol if nadolol is unavailable, should be the preferred β-blocker for treating symptomatic children with CPVT.

RASopathies are multisystemic disorders caused by germline mutations in genes linked to the RAS/mitogen-activated protein kinase pathway. Diagnosis of RASopathy can be triggered by clinical clues ("red flags") which may direct the clinician toward a specific gene test. Compared with sarcomeric hypertrophic cardiomyopathy, hypertrophic cardiomyopathy in RASopathies (R-HCM) is associated with higher prevalence of congestive heart failure and shows increased prevalence and severity of left ventricular outflow tract obstruction. Biventricular involvement and the association with congenital heart disease, mainly pulmonary stenosis, have been commonly described in R-HCM. The aim of this review is to assess the prevalence and unique features of R-HCM and to define the available therapeutic options.

Aims Patients with repaired Tetralogy of Fallot (rToF) tend to have a decent life free of limitations. In asymptomatic individuals, cardiac magnetic resonance imaging (MRI) is used to determine if pulmonary valve replacement (PVR) is necessary. Cardiopulmonary exercise testing (CPET) could aid in determining the extent of functional impairment. Methods and results rToF patients who had an MRI and CPET between 2019 and 2021 in a brief interval ( Conclusion In rToF patients with moderate–severe PR, NYHA class I, preserved RVEF, a slight reduction in exercise tolerance was detected. OUES could also be valuable to this population. A positive association was found between RV dilation and exercise performance up to 160 ml/m2 of RVEDVi, suggesting that perhaps at this cut-off value of RVEDVi, PVR could start being considered.

Aims: Children presenting with hypertrophic cardiomyopathy (HCM) in infancy are reported to have a poor prognosis, but this heterogeneous group has not been systematically characterized. This study aimed to describe the aetiology, phenotype, and outcomes of infantile HCM in a well-characterized multicentre European cohort. Methods and results: Of 301 children diagnosed with infantile HCM between 1987 and 2019 presenting to 17 European centres [male n=187 (62.1%)], underlying aetiology was non-syndromic (n=138, 45.6%), RASopathy (n=101, 33.6%), or inborn error of metabolism (IEM) (n=49, 16.3%). The most common reasons for presentation were symptoms (n=77, 29.3%), which were more prevalent in those with syndromic disease (n=62, 61.4%, P&nbsp

Aims Different authors have described three-dimensional (3D) voltage mapping of the Koch’s triangle (KT) in order to find low-voltage bridges (LVBs) as targets for a successful transcatheter ablation (TCA) of the slow pathway (SP) in children. Recently, the advisor high density (HD) Grid™ mapping catheter was introduced as new multipolar catheter for HD mapping. The aim of the study was to describe our preliminary experience with the use of HD Grid™ catheter in LVB and electrophysiologically guided cryoablation of SP in children. Methods and results Twenty-one children (mean age 13 ± 3 years) with atrioventricular nodal re-entrant tachycardia (AVNRT) underwent cryoablation of SP guided by voltage HD mapping of the KT using HD Grid™ catheter. In order to better highlight the differences with conventional mapping, point collection was performed in each patient with this new multipolar catheter and with a quadripolar catheter. The conventional mapping collected 871 ± 262 points and used 211 ± 80 points in 887 ± 275 s, whereas HD mapping collected 7468 ± 2947 points, using 604 ± 165 points in 513 ± 181 s (P Conclusions Our preliminary experience shows that HD mapping is faster and offers higher spatial resolution and definition. Procedural time can be reduced maintaining the TCA safe, with reduced fluoroscopy use, and successful.

Aims The aim of the study was to analyse our recent single-centre experience about epicardial posterior-septal accessory pathways transcatheter ablation in children and young patients using radiofrequency through the coronary sinus, in order to understand which mapping and ablation strategy is associated with higher success rate and safety. Methods and results We reviewed all the cases of ablation of overt accessory pathways (in Wolff–Parkinson–White syndrome) with epicardial posterior-septal localization performed in children or young patients at our institution in the last 5 years. Twenty-two paediatric patients (mean age: 13 ± 3 years) with epicardial posterior-septal accessory pathways (15 in coronary sinus and 7 in the Middle Cardiac Vein) underwent radiofrequency transcatheter ablation with CARTO 3TM. Acute success rate was 77%. No patient was lost to follow-up (mean time 14.4 ± 9 months). The recurrence rate was 18%. Two patients underwent a successful redo-procedure; the overall long-term success rate was 68%. NAVISTAR® catheter presented the highest acute success rate in the coronary sinus. NAVISTAR SMARTTOUCH® was the only catheter that did not present recurrences after the acute success and it was successfully used in two patients previously unsuccessfully treated with a NAVISTAR THERMOCOOL®. Integration with angio-CT of coronary sinus branches obtained with CARTOMERGE was associated with higher success rate in patients with a previous failed ablation attempt. Conclusions Epicardial posterior-septal accessory pathways can be successfully treated with transvenous radiofrequency ablation in more than half of the cases in children/young patients. Acute success rate does not seem to depend on catheters used but contact-force catheter seems to be useful in cases with recurrences. Image integration with cardiac-CT reconstruction of coronary sinus branches anatomy can be useful to better guide ablation in case of previously failed attempts.

Aims Arrhythmogenic cardiomyopathy (ACM) is a rare disease in children. The purpose of this study is to describe the main features of our paediatric patients with ACM providing a contribution for diagnostic work-up and therapeutic decisions. Methods and results Eligibility criteria of the study was ACM diagnosed at age Conclusions Paediatric ACM can be diagnosed in the majority of cases secondary to: incidental finding of minor arrhythmias or due to positive family history. PVCs burden is not elevated and exercise-induced arrhythmias occur in a minority of patients. ICD may be indicated in most patients even if follow-up during the paediatric age can be reassuring. Multicentric observation is highly needed to derive conclusions in children.

Background: Monosomy 1p36 syndrome is now considered the most common terminal deletion syndrome, with an estimated incidence of 1 in 5000. Cardiac involvement is well described in the literature mainly in terms of congenital heart defects (CHDs) and cardiomyopathies (CMPs). Few data in the literature describe the potential progressive nature of aortic dilatation (root and ascending aorta) in 1p36 deletion syndrome. SKI harboured in the deleted region might play a predisposing factor for this aspect. Methods: we reviewed the aortic aspect both in the literature and in our cohort, where major attention to the aortic abnormalities was given through dedicated echocardiographic measurements even in previously screened individuals. Results: aortic involvement in 1p36 deletion syndrome was described in the literature three times within the CHD context. We observed three additional patients from our cohort (three out of nine patients) with aortic dilatation. All patients with dilated aorta had SKI haploinsufficiency within the deleted region. Conclusions: at long-term outcome and with a growing population of this rare disease, this association (1p36 deletion and aortic dilatation) might represent a major concern especially in terms of risk stratification and the potential need for specific management (conservative pharmacologic and eventually surgical) whenever indicated. The present study suggests the need for detailed multicentric studies and indication to periodic echocardiographic screening in addition to baseline tests, especially in individuals with deletions harbouring SKI.

The genetic background of congenital heart diseases (CHDs) is extremely complex, heterogenous, and still majorly to be determined. CHDs can be sporadic or familial. In this article we discuss in detail the phenotypic spectrum of selected genes including MYH7, GATA4, NKX2-5, TBX5, and TBX20. Our goal is to offer the clinician a general overview of the clinical spectrum of the analyzed topics that are traditionally known as causative for CHDs but we underline in this review the possible progressive functional (cardiomyopathy) and electric aspects (arrhythmias) caused by the genetic background.

Deletions involving the distal portion of the short arm of chromosome 8(8p23.1) show a high phenotypic variability. Congenital heart diseases (CHD) are often described. GATA4 when mutated or deleted is reported to be involved in cardiac morphogenesis. Only twice, left ventricular non compaction (LVNC) was reported in literature in association with 8p23.1 deletion. The present cohort includes five new patients with 8p23.1 deletions including GATA4. The spectrum of CHD is variable. Moreover, in four patients, LV hypertrabeculation was detected and in the fifth LVNC was recognized. Literature revision identified 45 patients with 8p23.1 deletions (encompassing GATA4) and heart involvement. It included wide spectrum of CHD including: heterotaxy spectrum 7/45 (15, 6%), atrioventricular canal 14/45 (balanced 3/45 including two of them with hypoplastic aortic arch; unbalanced 4/45, Fallot-AVC 1/45, partial AVC 3/45, unspecified 3/45), predominant major left heart lesions included 2/45 (4, 4%): interrupted aortic arch and hypoplastic left heart syndrome. Left ventricular hypertrabeculation might be potentially underestimated in patients with 8p23.1 deletion. These might suggest the importance of including microarray analysis in this group of patients. Moreover, 8p23.1 microdeletion or GATA4 variants can be considered in heterotaxy genetic panels.

Pericarditis with pericardial effusion in SARS CoV-2 infection is a well-known entity in adults. In children and adolescents, only a few cases have been reported. Here, we present here a case of a 15-year-old girl affected by Sotos syndrome with pre-tamponed pericardial effusion occurred during SARS-CoV-2 infection. A possible relation between SARS-CoV-2 pericarditis and genetic syndromes, as a major risk factor for the development of severe inflammation, has been speculated. We emphasize the importance of active surveillance by echocardiograms when SARS-CoV-2 infection occurs in combination with a genetic condition.

AIM: This study evaluates the risk factors associated with right ventricular (RV) dilation and dysfunction leading to pulmonary valve replacement (PVR) or adverse cardiac events in repaired Tetralogy of Fallot (rToF) patients.METHODS: Data from all rToF patients who underwent magnetic resonance imaging (MRI) evaluation at our hospital between February 2007 and September 2020 were collected.RESULTS: Three hundred and forty-two patients (60% males, 42% older than 18 years), with a median age of 16 years (IQR 13-24) at the time of MRI, were included. All patients underwent complete repair at a median age of 8 months (IQR 5-16), while palliation was performed in 56 patients (16%). One hundred and forty-four patients (42%) subsequently received pulmonary valve replacement (PVR). At the multivariate analysis, male gender was an independent predictor for significant RV dilation, RV and left ventricular (LV) dysfunction. Transventricular ventricular septal defect (VSD) closure and previous palliation significantly affected LV function and RV size, respectively. Male gender and the transventricular VSD closure were independent predictors for PVR.CONCLUSIONS: Male gender and surgical history (palliation, VSD closure approach) significantly affected the long-term outcomes in rToF patients and should be taken into consideration in the follow-up management and in PVR timing in this patient population.

Neuromuscular disorders (NMDs) are highly heterogenous from both an etiological and clinical point of view. Their signs and symptoms are often multisystemic, with frequent cardiac involvement. In fact, childhood onset forms can predispose a person to various progressive cardiac abnormalities including cardiomyopathies (CMPs), valvulopathies, atrioventricular conduction defects (AVCD), supraventricular tachycardia (SVT) and ventricular arrhythmias (VA). In this review, we selected and described five specific NMDs: Friedreich’s Ataxia (FRDA), congenital and childhood forms of Myotonic Dystrophy type 1 (DM1), Kearns Sayre Syndrome (KSS), Ryanodine receptor type 1-related myopathies (RYR1-RM) and Laminopathies. These changes are widely investigated in adults but less researched in children. We focused on these specific topics due their relative frequency and their potential unexpected cardiac manifestations in children. Moreover these conditions present different inheritance patterns and mechanisms of action. We decided not to discuss Duchenne and Becker muscular dystrophies due to extensive work regarding the cardiac aspects in children. For each described NMD, we focused on the possible cardiac manifestations such as different types of CMPs (dilated-DCM, hypertrophic-HCM, restrictive-RCM or left ventricular non compaction-LVNC), structural heart abnormalities (including valvulopathies), and progressive heart rhythm changes (AVCD, SVT, VA). We describe the current management strategies for these conditions. We underline the importance, especially for children, of a serial multidisciplinary personalized approach and the need for periodic surveillance by a dedicated heart team. This is largely due to the fact that in children, the diagnosis of certain NMDs might be overlooked and the cardiac aspect can provide signs of their presence even prior to overt neurological diagnosis.

Background Congenital heart disease (CHD) is the most common congenital anomaly at birth, affecting approximately 1% of live births. In recent decades great medical and surgical advances have significantly increased life expectancy, shifting healthcare professionals' and researchers’ interests in patients' Quality of Life (QoL). The main aims of our study were to evaluate generic and condition-specific QoL in a group of Italian children and adolescents with CHD and their parents and examine the level of agreement and directional disagreement between child/adolescent and parents reports on generic and condition-specific QoL. Methods A cross-sectional study was designed with CHD children and adolescents and their parents referred to the Cardiology Department of “Bambino Gesù” Children’s Hospital. The PedsQL scale was used, including generic (PedsQL 4.0) and cardiac-specific modules (PedsQL 3.0) were administered to patients and caregivers. A Kruskal–Wallis test was used to compare generic and cardiac module scores between patients with different ages, CHD diagnoses, and between patients who underwent surgery interventions and/or are currently taking cardiac medications. Results 498 families were enrolled in this study. On average, patients reported a good level of generic and condition-specific QoL, as well as their mothers and fathers. Children aged between 5–7 years old reported lower generic and cardiac-specific total QoL levels than children aged 8–12 years and adolescents (13–18 years). With regard to the agreement, patient-parent agreement on condition-specific QoL ranged from 25 to 75% while on generic QoL, it ranged from 19 to 76%. The highest percentage of disagreement between parents and children was found in patients aged 5–7 years old, both for condition-specific and generic QoL rates. Conclusions Our study contributed to the growing body of knowledge on QoL in CHD, emphasizing the need for these families to receive support from multidisciplinary standardized care, including psychological consultations and support.

Murine B-1 cells produce IgMs that inactivate oxidation-specific epitopes and protect against atherosclerosis. Despite compelling data that IgM to MDA-LDL (IgM MDA-LDL ) is inversely associated with coronary artery disease (CAD) and cardiovascular (CV) events in human, the human B cell subtype that produces IgM MDA-LDL is unknown. Here, we utilized mass cytometry to identify the 11 circulating human B cell subtypes and discovered that only the frequency of CD20 + CD27 + IgM + cells was associated with IgM MDA-LDL levels. Notably, high expression of CD24, a GPI-anchored sialoglycoprotein, was associated with IgM MDA-LDL (r = 0.57, p = 0.002) and inversely associated with CAD severity (r = -0.58, p=0.001). Adoptive transfer (AT) of sorted CD20 + CD27 + IgM + CD24hi (B 27+IgM+CD24hi ) and CD24lo/- (B 27+IgM+CD24lo/- ) human B cells into humanized mice demonstrated that CD24 is critical for trafficking to the spleen and IgM production. Bulk RNAseq coupled with pathway analysis of B 27+IgM+CD24hi and B 27+IgM+CD24lo/- cells revealed enhanced BCR and CCR6 signaling in B 27+IgM+CD24hi . Imaging flow cytometry indicated colocalization between CD24 and CCR6 which was abrogated by CD24 blocking antibody (CD24mAb). Trans-well migration and internalization assays demonstrated that CD24 blockade increased CCL20-induced CCR6 internalization (p < 0.05, n =4), and reduced CCL20-induced migration of B 27+IgM+CD24hi cells (p < 0.05, n =4). CD24mAb treatment of B 27+IgM+CD24hi cells prior to AT into humanized mice also reduced the amount of surface CCR6 on B 27+IgM+CD24hi cells in vivo (p < 0.05, n = 4). Both CCR6 knockout and CD24 inhibition of B 27+IgM+CD24hi cells reduced migration to the spleen (p < 0.05, n = 4), and plasma level of human IgM (p = 0.057, n = 4). Lastly, single cell multi-omics sequencing of PBMCs from 60 CAD subjects revealed elevated CCR6 and IgM signaling in B 27+IgM+CD24hi cells in subjects with less severe CAD. Results provide the first evidence for a role for CD24 in regulating CCR6-mediated B cell homing to the spleen, IgM production and CAD in humans. Findings may have important implications for the new CD24 immunotherapy entering clinical trials and raise the possibility that augmenting CD24 and/or CCR6 on B 27+IgM+ cells may be an effective atheroprotective strategy.

Objective: Murine data, prospective epidemiological studies, and genetic association data support a potential causal role of IL-6 signaling in atherosclerosis development. IL-6 inhibitors have emerged as potential therapeutics for reducing events in both stable coronary artery disease (CAD) and acute coronary syndromes. IL-6-induced immune regulation plays an important role in atherosclerosis, however, a comprehensive map of IL-6 signaling in human immune cells is currently lacking. We developed a 32-antibody custom mass cytometry (CyTOF) panel to characterize IL-6 signaling across all major human immune cell subsets and applied it to identify IL-6-induced immune signatures linked with unstable atherosclerotic plaque. Methods: Peripheral blood mononuclear cells from healthy donors and subjects with CAD undergoing virtual histology-intravascular ultrasound imaging (IVUS-VH) were stimulated with vehicle and IL-6, stained, and ran in CyTOF. Unsupervised analysis algorithms (SPADE, UMAP, and Leiden clustering) were used to identify immune cell subsets and IL-6-induced intracellular phosphorylation status. Results: IL-6 induced STAT1 and STAT3 activation in CD4 and CD8 naïve T cell subsets and CD4 memory T subsets. Notably, we identified that IL-6 also activates STAT5 within the CD4 and CD8 naïve T subsets. IL-6 induced a much more robust activation of STAT1 as compared to STAT3 and STAT5. Other cell types such as CD14 + monocytes, and CD11c + , and CD123 + dendritic cells also showed IL-6-induced STAT activation. IL-6-induced phosphorylation of STAT1 and STAT3 in a novel PD-1 + CD4 + effector memory T cell subtype was associated with higher CAD burden and unstable plaque features. Conclusions: Findings are significant for mechanistic insights into IL-6-induced inflammation and may enable discovery of new approaches to reduce inflammation in CAD and other pathologies.

Recent advances in understanding the genetic causes and anatomic subtypes of cardiac defects have revealed new links between genetic etiology, pathogenetic mechanisms and cardiac phenotypes. Although the same genetic background can result in different cardiac phenotypes, and similar phenotypes can be caused by different genetic causes, researchers’ effort to identify specific genotype–phenotype correlations remains crucial. In this review, we report on recent advances in the cardiac pathogenesis of three genetic diseases: Down syndrome, del22q11.2 deletion syndrome and Ellis–Van Creveld syndrome. In these conditions, the frequent and specific association with congenital heart defects and the recent characterization of the underlying molecular events contributing to pathogenesis provide significant examples of genotype–phenotype correlations. Defining these correlations is expected to improve diagnosis and patient stratification, and it has relevant implications for patient management and potential therapeutic options.

PURPOSE Different authors have described three-dimensional (3D) voltage mapping of the Koch's triangle (KT) in order to find low-voltage bridges (LVB) as targets for a successful transcatheter ablation (TCA) of the slow pathway (SP) in children. Recently, the Advisor High Density (HD) Grid™ mapping catheter was introduced as new multipolar catheter for HD mapping. The aim of the study was to describe our preliminary experience with the use of HD Grid™ catheter in LVB and electrophysiologically guided cryoablation of SP in children. METHODS Twenty-one children (mean age 13±3 years) with atrioventricular nodal re-entrant tachycardia (AVNRT) underwent cryoablation of SP guided by voltage HD mapping of the KT using HD Grid™ catheter. In order to better highlight the differences with conventional mapping, point collection was performed in each patient with this new multipolar catheter and with a quadripolar catheter. RESULTS The conventional mapping collected 871±262 points and used 211±80 points in 887±275 s, whereas HD mapping collected 7468±2947 points, using 604±165 points in 513±181 s (p

Noonan syndrome (NS) is caused by mutations in more than 10 genes, mainly PTPN11, SOS1, RAF1, and RIT1. Congenital heart defects and cardiomyopathy (CMP) are associated with significant morbidity and mortality in NS. Although hypertrophic CMP has "classically" been reported in association to RAF1, RIT1, and PTPN11 variants, SOS1 appears to be poorly related to CMP. Patients with NS attending our Center from January 2013 to June 2018 were eligible for inclusion if they carried SOS1 variants and presented with-or developed-CMP. Literature review describing the co-existence of SOS1 mutation and CMP was also performed. We identified six patients with SOS1 variants and CMP (male to female ratio 2:1) including two novel variants. CMP spectrum encompassed: (a) dilated CMP, (b) nonobstructive hypertrophic CMPs, and (c) obstructive hypertrophic CMPs. Survival is 100%. Literature review included 16 SOS1 mutated in CMP. CMP, mainly hypertrophic, has been often reported in association to RAF1, RIT1, and PTPN11 variants. Differently from previous reports, due to the frequent association of SOS1 variants and CMP in our single center experience, we suggest potential underestimated proportion of SOS1 in pediatric CMPs.

OBJECTIVE A common method of distress monitoring in cancer patients relies on static and retrospective data collected in-person at the time of a health care provider appointment. Relatively little work has examined the potential usefulness of mobile distress monitoring using cancer patients' smartphones. The current study deployed longitudinal distress monitoring using secure text messaging. METHODS In an observational study, a total of 52 cancer patients receiving active cancer treatment (Mage = 58, 62% female) received a text message once a week for 4 weeks. Text messages contained a secure link to complete online the Patient Health Questionnaire-4 (PHQ-4), a commonly used distress screener. RESULTS Cancer patients completed a distress screener 75% of the time they received a text message. On average, it took less than a minute to complete each mobile distress screener. Geolocation data indicated that cancer patients completed distress screeners across a range of locations. Analyses of model fit of distress scores indicated significant heterogeneity in variability of distress scores over time and across cancer patients (AIC = 630.5). Quantitative feedback from cancer patients at the end of the study indicated high ease of use, ease of learning, and satisfaction of completing mobile distress screeners. CONCLUSIONS These findings support the use of secure text messaging to monitor longitudinal, out of clinic, distress in cancer patients. Findings also highlight the importance of mobile-based approaches to distress screening in order to maximize opportunities to intervene.

Classic ECG interpretation is based on identification of waveforms and deductive analysis of the electrical events the waveforms represent. The more in depth the understanding of electrophysiologic cellular interactions, the more precise the interpretation of ECG tracing. Surface ECG has limitations; yet, it is accurate in representing myocytes' pathologic behaviors. Recent advances have improved understanding of arrhythmias by reconstructing their mechanisms of induction and maintenance and exploring cellular channel dysfunction. Translating this knowledge to ECG analysis will create the link that allows ECG interpretation to reach the level of precision electrocardiology. This article presents cases illustrating new techniques for electrophysiologists.

Recessive variants in LTBP2 are associated with eye-restricted phenotypes including (a) primary congenital glaucoma and (b) microspherophakia/megalocornea and ectopia lentis with/without secondary glaucoma. Nosology of LTBP2 pathology in humans is apparently in contrast with the consolidated evidence of a wide expression of this gene in the developing embryo. Accordingly, in previously published patients with LTBP2-related eye disease, additional extraocular findings have been occasionally reported and include, among others, high-arched palate, tall stature, and variable cardiac involvement. Anyway, no emphasis was put on such systemic manifestations. Here, we report two unrelated Roma/Gypsy patients first ascertained for a multisystem disorder mainly characterized by primary congenital glaucoma, complex congenital heart defect, tall stature, long fingers, skin striae and dystrophic scarring, and resembling Marfan syndrome. Heart involvement was severe with polyvalvular heart dysplasia in one, and transposition of great arteries, thoracic arterial tortuosity, polyvalvular heart dysplasia, and neo-aortic root dilatation in the other. Both patients were homozygous for the recurrent c.895C>T[p.(R299X)] variant, typically found in individuals of Roma/Gypsy descent with an eye-restricted phenotype. Our findings point out LTBP2 as responsible of a systemic phenotype coherent with the community of syndromes related to anomalies in genes involved in the TGFβ-pathway. Among these disorders, LTBP2-related systemic disease emerges as a distinct condition with expanding prognostic implications and autosomal recessive inheritance.

Background Friedreich Ataxia (FRDA) is the most common form of ataxia in late childhood. Neurological manifestations often precede cardiac involvement, presenting mainly as hypertrophic cardiomyopathy. Methods We describe a toddler with apparently isolated severe heart failure, successfully managed with heart transplant (HT). Although well described in adolescents and adults, onset of FRDA is very uncommon in toddlers and neurological ataxic features are predominant. The presenting symptom of cardiomyopathy is very rare. Similar history is rarely reported in literature, that we described, including an aggressive cardiomyopathy in children younger than 5years-old. Results Our patient was diagnosed with FRDA at a postoperative stage due to minimal neurological manifestations. Moreover, the novelty of this study lies in demonstrating a major DNA triplet repeat expansion in skeletal muscle compared to DNA from peripheral blood leukocytes. These results support the concept that triplet repeat expansion is variable among different tissues in FRDA, and in our case it was more expanded in the post mitotic muscular tissue than in blood cells. Conclusions We believe on the importance of taking in consideration this rare condition even in a toddler with apparently isolated cardiomyopathy and especially when conventional investigations give negative results. We discuss potential trigger effect of heart transplant as a precipitating factor in manifesting neurological symptoms. This observation corresponds to our experience and relates to three patients described so far (the third patient died suddenly). Early onset cardiomyopathy with FRDA should increase awareness of this rare condition and we highlight HT successful outcome. Further reports are needed to delineate this rare condition in youngsters.

IL-1β is a key mediator of the cytokine storm linked to high morbidity and mortality from COVID-19 and IL-1β blockade with Anakinra and Canakinumab during COVID-19 infection has entered clinical trials. Using mass cytometry of human peripheral blood mononuclear cells, we identified effector memory CD4(+) T cells and CD4(-)CD8(low/-)CD161(+) T cells, specifically those positive for the chemokine receptor CCR6, as the circulating immune subtypes with the greatest response to IL-1β. This response manifested as increased phosphorylation and thus activation of the proinflammatory transcription factor NF-κB and was also seen in other subsets, including CD11c(+) myeloid dendritic cells, classical monocytes, two subsets of natural killer cells (CD16(-)CD56(bright)CD161(-) and CD16(-)CD56(dim)CD161(+)), and lineage(-) (Lin(-)) cells expressing CD161 and CD25. IL-1β also induced a rapid but less robust increase in the phosphorylation of the kinase p38 as compared to that of NF-κB in most of these immune cell subsets. Prolonged IL-1β stimulation increased the phosphorylation of the transcription factor STAT3 and to a lesser extent that of STAT1 and STAT5 across various immune cell types. IL-1β-induced production of IL-6 likely led to the activation of STAT1 and STAT3 at later time points. Interindividual heterogeneity and inhibition of STAT activation by Anakinra raises the possibility that assays measuring NF-κB phosphorylation in response to IL-1β in CCR6(+) T cell subtypes could identify those patients at higher risk of cytokine storm and most likely to benefit from IL-1β-neutralizing therapies.

We report a unique case of a 6-year-old male child with aborted sudden cardiac death due to ventricular fibrillation. A rare anomalous aortic origin of the right coronary artery was detected and supposed to be the cause of the malignant arrhythmia. Clinical exome sequencing did not reveal any pathogenic variant related to channelopathies nor other known heart-related genes. The patient underwent cardiac surgery and a cardiac defibrillator was implanted for secondary prevention.

Background: The COVID-19 pandemic had a significant impact on the population’s ability to be physically active. Purpose: Evaluate the effect of the COVID-19 mitigation measures on exercise tolerance in patients with congenital heart disease (CHD). Materials and methods: All subjects (880, 6–18 years old) who performed a stress test at our hospital from October 2020 to February 2021 and had a similar test one year earlier were enrolled. A questionnaire on the degree of physical activity carried out in 2020 concerning the period prior to the pandemic was compiled. Exercise tolerance and the main anthropometric parameters between the first and second tests were compared. Results: 110 subjects (11.9 ± 4.1 years) were included in the study. The percentage of patients engaged in regular physical activity (RPA) decreased significantly during the pandemic (p &lt, 0.001), and BMI increased significantly (p &lt, 0.001), except among the subjects who began RPA during the lockdown, whereas test duration did not decrease significantly overall but increased in this last subgroup (p &lt, 0.05) Conclusions: The COVID-19 lockdown led to a less active lifestyle with a significant increase in BMI in our group of CHD. These data could have negative effects on the risk profile of this population. RPA practiced at home seems to be effective in counteracting such effects.

Aims The 12-lead electrocardiogram (ECG) is routinely performed in children with hypertrophic cardiomyopathy (HCM). An ECG risk score has been suggested as a useful tool for risk stratification, but this has not been independently validated. This aim of this study was to describe the ECG phenotype of childhood HCM in a large, international, multi-centre cohort and investigate its role in risk prediction for arrhythmic events. Methods and results Data from 356 childhood HCM patients with a mean age of 10.1 years (±4.5) were collected from a retrospective, multi-centre international cohort. Three hundred and forty-seven (97.5%) patients had ECG abnormalities at baseline, most commonly repolarization abnormalities (n = 277, 77.8%); left ventricular hypertrophy (n = 240, 67.7%); abnormal QRS axis (n = 126, 35.4%); or QT prolongation (n = 131, 36.8%). Over a median follow-up of 3.9 years (interquartile range 2.0–7.7), 25 (7%) had an arrhythmic event, with an overall annual event rate of 1.38 (95% CI 0.93–2.04). No ECG variables were associated with 5-year arrhythmic event on univariable or multivariable analysis. The ECG risk score threshold of >5 had modest discriminatory ability [C-index 0.60 (95% CI 0.484–0.715)], with corresponding negative and positive predictive values of 96.7% and 6.7% Conclusion In a large, international, multi-centre cohort of childhood HCM, ECG abnormalities were common and varied. No ECG characteristic, either in isolation or combined in the previously described ECG risk score, was associated with 5-year sudden cardiac death risk. This suggests that the role of baseline ECG phenotype in improving risk stratification in childhood HCM is limited.

The field of electrophysiology (EP) in paediatric cardiology patients and adults with congenital heart disease is complex and rapidly growing. The current recommendations for diagnostic and invasive electrophysiology of the working group for Cardiac Dysrhythmias and Electrophysiology of the Association for European Paediatric and Congenital Cardiology acknowledges the diveristy of European countries and centers. These training recommendations can be fulfilled in a manageable period of time, without compromising the quality of training required to become an expert in the field of paediatric and congenital EP and are for trainees undergoing or having completed accredited paediatric cardiologist fellowship. Three levels of expertise, the training for General paediatric cardiology EP, for non-invasive EP and invasive EP have been defined. This Association for European EP curriculum describes the theoretical and practicsal knowledge in clinical EP; catheter ablation, cardiac implantable electronic devices, inherited arrhythmias and arrhythmias in adults with congenital heart defects for the 3 levels of expertise.

Background Brugada syndrome (BrS) is an inheritable disease with an increased risk of sudden cardiac death. Although several score systems have been proposed, the management of children with BrS has been inconsistently described. Objective The purpose of this study was to identify the characteristics, outcome, and risk factors associated with cardiovascular and arrhythmic events (AEs) in children younger than 12 years with BrS. Methods In this single-center case series, all children with spontaneous or drug/fever-induced type 1 Brugada electrocardiographic (ECG) pattern and younger than 12 years at the time of diagnosis were enrolled. Results Forty-three patients younger than 12 years at the time of diagnosis were included. The median follow-up was 3.97 years (interquartile range 2–12 years). In terms of first-degree atrioventricular block, premature beats, nonmalignant AEs, malignant AEs, and episodes of syncope, no significant differences were observed either between patients with spontaneous and drug/fever-induced type 1 Brugada ECG pattern or between female and male patients (except a significant difference between female and male patients for first-degree atrioventricular block). A higher incidence of malignant AEs was observed in patients with syncope (3 of 8 [37.5%] vs 0 of 35 [0%]; P = .005) than in patients without syncope. SCN5A mutations were associated with a higher occurrence of malignant AEs (3 of 14 [21.4%] vs 0 of 25 [0%]; P = .04) compared with no SCN5A mutations. Conclusion A spontaneous type 1 Brugada ECG pattern is not associated with a higher incidence of syncope, first-degree atrioventricular block, premature beats, nonmalignant AEs, and malignant AEs than the drug/fever-induced type 1 Brugada ECG pattern. Syncope events are correlated with an increased incidence of malignant AEs. Moreover, SCN5A mutations are associated with a higher occurrence of malignant AEs.

Age-Associated B cells (ABCs: CD19+CD11c+) have recently been reported as a new subset of B cells with unique cell surface and transcriptional signatures. ABCs are mostly comprised of antigen experienced memory B cells that arise in response to microbial infections. ABCs have been reported to be elevated in autoimmune diseases, where in, these cells have characteristics of auto-antibody producing memory B cells. However, the role of ABCs during atherosclerosis has not be studied. Atherosclerosis is a chronic inflammatory disease and the major underlying cause for cardiovascular diseases (CVD). We for the first time report the role of ABCs in both atherosclerotic mice and in human CVD. Chow fed 50- and 100- week old, male, ApoEKO mice were used to study atherosclerosis. Lesion area was measured following Sudan-IV enface staining of aorta. 100-week-old mice developed significantly more disease than the 50-week-old mice. Further, through flow cytometric analysis ABCs were detected in spleen, bone marrow (BM) and blood of these mice. The frequency of ABCs from total B cells was significantly higher in all these tissue compartments in 100-week-old mice compared to 50-week-old mice. Additionally, most ABCs (>80 %) were actively proliferating cells (Ki67+), as compared to normal CD11c− B cells (~35 %). In mice, we observed a significant correlation of atherosclerosis disease levels with the frequency of ABCs in spleen (p=0.004, R2=0.61), BM (p=0.01, R2=0.53), and blood (p=0.0005, R2=0.75). In humans as well, the frequency of circulating ABCs was significantly higher in CVD subjects compared to non-CVD subjects. Results from this study suggest a strong association of ABCs with aggravated atherosclerosis in both murine models and humans with CVD.

BackgroundDetailed understanding of the immune response to SARS-CoV-2, the cause of coronavirus disease 2019 (COVID-19), has been hampered by a lack of quantitative antibody assays.ObjectiveTo develop a quantitative assay for IgG to SARS-CoV-2 proteins that could readily be implemented in clinical and research laboratories.MethodsThe biotin-streptavidin technique was used to conjugate SARS-CoV-2 spike receptor-binding-domain (RBD) or nucleocapsid protein to the solid-phase of the ImmunoCAP resin. Plasma and serum samples from patients with COVID-19 (n=51) and samples from donors banked prior to the emergence of COVID-19 (n=109) were used in the assay. SARS-CoV-2 IgG levels were followed longitudinally in a subset of samples and were related to total IgG and IgG to reference antigens using an ImmunoCAP 250 platform.ResultsPerformance characteristics demonstrated 100% sensitivity and 99% specificity at a cut-off level of 2.5 µg/mL for both SARS-CoV-2 proteins. Among 36 patients evaluated in a post-hospital follow-up clinic, median levels of IgG to spike-RBD and nucleocapsid were 34.7 µg/mL (IQR 18-52) and 24.5 µg/mL (IQR 9-59), respectively. Among 17 patients with longitudinal samples there was a wide variation in the magnitude of IgG responses, but generally the response to spike-RBD and to nucleocapsid occurred in parallel, with peak levels approaching 100 µg/mL, or 1% of total IgG.ConclusionsWe have described a quantitative assay to measure IgG to SARS-CoV-2 that could be used in clinical and research laboratories and implemented at scale. The assay can easily be adapted to measure IgG to novel antigens, has good performance characteristics and a read-out in standardized units.

Background: Atherosclerotic plaques in mice and humans contain natural killer (NK) cells. Data on the role of NK cells in atherosclerosis using different transgenic mice models is inconsistent. Some studies showed that NK cells augment atherosclerosis through their cytotoxic potential, while others reported no effect. Evidence in humans indicates that NK cells are atherogenic. Frequency of NK cells and expression of the activating NK cell receptors are associated with severe disease and symptomatic carotid atherosclerotic plaques in humans. Hypothesis: We tested if coronary artery disease (CAD) subjects with necrotic plaques have a higher frequency of the circulating NK cells. Methods: We performed mass cytometry on peripheral blood mononuclear cells from matched CAD subjects with low and high (n=9 each) necrotic plaque content as determined by intravascular ultrasound-virtual histology. Results: CAD subjects with high necrotic plaques have significantly higher atheroburden, stenosis, calcium, fatty plaque content, and lower plaque fibrosis. Interestingly, CAD subjects with high necrotic plaques exhibited a significantly higher frequency of the CD56 bright NK cells as compared to those with low necrotic plaques (4.618 ± 0.625 vs 2.481 ± 0.37; p=0.011). Moreover, frequency of CD25 + NK cells also trended to be higher in subjects with high necrotic plaques. The frequency of the cytotoxic CD56 dim NK cells did not differ between the two groups. Correlation analyses demonstrated a significant positive association of CD56 bright NK cells with atheroburden (r=0.43; p=0.04), stenosis (r=0.58; p=0.005), plaque necrotic (r=0.71; p=0.002), calcium contents (r=0.73; p=0.0001), and a negative association with the plaque fibrous content (r=0.71; p= 0.0003). CD25 + NK cells also showed similar trending associations with burden, stenosis and plaque features. Conclusions: Our data provides yet another evidence of the atherogenic role of NK cells in humans and indicates that the CD56 bright NK cells may contribute to the development of a vulnerable plaque. CD56 bright NK cells produce proinflammatory cytokines including IFN-γ and TNF-α and cytotoxic enzymes that may contribute to increased inflammation, cell activation, and apoptosis within the plaque.

Transcatheter ablation (TA) for treatment of pediatric tachyarrhythmias was first introduced in the early 1990s. Since then, its use as an alternative to antiarrhythmic drugs to treat supraventricular tachycardias caused by accessory pathway has been increasing. Nowadays, TA can be performed with high success rates and low complication rates even in very young children. Recently, the use of different types of energy (radiofrequency and cryoenergy), special ablation catheters, and 3D nonfluoroscopic mapping systems equipped with high technological tools has further improved safety and efficacy of TA, especially in difficult substrates and in patients with congenital heart disease.

Background: The X-linked Danon disease manifests by severe cardiomyopathy, myopathy, and neuropsychiatric problems. We designed this registry to generate a comprehensive picture of clinical presentations and outcome of patients with Danon disease in cardiomyopathy centers throughout Europe. Methods: Clinical and genetic data were collected in 16 cardiology centers from 8 European countries. Results: The cohort comprised 30 male and 27 female patients. The age at diagnosis was birth to 42 years in men and 2 to 65 in women. Cardiac involvement was observed in 96%. Extracardiac manifestations were prominent in men but not in women. Left ventricular (LV) hypertrophy was reported in 73% of male and 74% of female patients. LV systolic dysfunction was reported in 40% of men (who had LV ejection fraction, 34±11%) and 59% of women (LV ejection fraction, 28±13%). The risk of arrhythmia and heart failure was comparable among sexes. The age of first heart failure hospitalization was lower in men (18±6 versus 28±17 years; P Conclusions: Danon disease presents earlier in men than in women and runs a malignant course in both sexes, due to cardiac complications. Cardiomyopathy features, heart failure and arrhythmia, are similar among the sexes. Clinical diagnosis and management is extremely challenging in women due to phenotypic diversity and the absence of extracardiac manifestations.