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Background  The SelectSecure lumenless 3830 pacing lead is often considered to be the pacing lead of choice for transvenous pacing in children because of its small diameter, lead strength, and reliable long-term sensing and pacing characteristics. One of the potential long-term pitfalls of a sturdy pacing lead is relative retraction with growth in children resulting in late lead dislodgement. Case summary  We report two cases of late SelectSecure 3830 lead dislodgement at 11.8 years (Case 1) and 8.8 years (Case 2), respectively, post the initial implantation. Case 1 was diagnosed with congenital complete heart block (CHB) at 9 months old when he presented with unconfirmed diphtheria infection. Case 2 was diagnosed with CHB at 14 weeks of age with positive maternal anti-Ro antibodies. Both patients underwent implantation of a transvenous permanent pacemaker implantation with Medtronic SelectSecure 3830 lead due to symptomatic bradycardia. Apart from a pulse generator change at 8.5 years (Case 1) and 7 years (Case 2), respectively, post-implant due to normal battery depletion, both patients are well in the interim. Discussion  As part of the pacemaker follow-up for rapidly growing children, we recommend more frequent surveillance of lead 'tautness' by chest radiography especially in children with CHB with no underlying heart rhythm. [ABSTRACT FROM AUTHOR]

Objectives To investigate fetal/perinatal and maternal outcomes from a large multicentre cohort of women diagnosed with UCTD. Methods This multicentre retrospective cohort study describes the outcomes of 224 pregnancies in 133 consecutive women with a diagnosis of UCTD, positive for ANA and aged <45 years old at study inclusion. Results Of the 224 pregnancies analysed, 177 (79%) resulted in live births, 45 (20.1%) in miscarriages (defined as pregnancy loss before 12 weeks' gestation), 2 (0.9%) in stillbirths (pregnancy loss after 20 weeks' gestation) and 6 (2.7%) cases showed intrauterine growth restriction. Miscarriages and stillbirths were strongly associated with the presence of aPL and ENA antibodies (P  < 0.05). Maternal pregnancy complications were as follows: 5 (2.2%) cases developed pre-eclampsia, 11 (4.9%) cases gestational hypertension and 12 (5.4%) cases gestational diabetes. Joint involvement represented the most frequent clinical manifestation of the cohort (57.9%), followed by RP (40.6%), photosensitivity (32.3%) and haematological manifestations (27.1%). The rate of disease evolution of our cohort from a diagnosis of UCTD to a diagnosis of definite CTD was 12% within a mean time of 5.3 ± 2.8 years. With a total follow-up after first pregnancy of 1417 patient-years, we observed the evolution to a defined CTD in one out of every 88 patient- years. Conclusion In our multicentre cohort, women with UCTD had a live birth rate of 79%. Women with UCTD should be referred to specialist follow-up when planning a pregnancy. ENA profiling and aPL testing should be mandatory in this setting, and further therapeutic approaches and management should be planned accordingly. [ABSTRACT FROM AUTHOR]

Aims Investigating human heart development and applying this to deviations resulting in disease is incomplete without molecular characterization of the cell types required for normal functioning. We investigated foetal human heart single-cell transcriptomes from mid-gestational healthy and anti-SSA/Ro associated congenital heart block (CHB) samples. Methods and results Three healthy foetal human hearts (19th to 22nd week of gestation) and one foetal heart affected by autoimmune-associated CHB (21st week of gestation) were subjected to enzymatic dissociation using the Langendorff preparation to obtain single-cell suspensions followed by 10× Genomics- and Illumina-based single-cell RNA-sequencing (scRNA-seq). In addition to the myocytes, fibroblasts, immune cells, and other minor cell types, previously uncharacterized diverse sub-populations of endothelial cells were identified in the human heart. Differential gene expression analysis revealed increased and heterogeneous interferon responses in varied cell types of the CHB heart compared with the healthy controls. In addition, we also identified matrisome transcripts enriched in CHB stromal cells that potentially contribute to extracellular matrix deposition and subsequent fibrosis. Conclusion These data provide an information-rich resource to further our understanding of human heart development, which, as illustrated by comparison to a heart exposed to a maternal autoimmune environment, can be leveraged to provide insight into the pathogenesis of disease. [ABSTRACT FROM AUTHOR]

Objectives In this study we aimed to investigate foetal and maternal pregnancy outcomes from a large multicentre cohort of women diagnosed with MCTD and anti-U1RNP antibodies. Methods This multicentre retrospective cohort study describes the outcomes of 203 pregnancies in 94 consecutive women ever pregnant who fulfilled the established criteria for MCTD with confirmed U1RNP positivity. Results The foetal outcomes in 203 pregnancies were as follows: 146 (71.9%) live births, 38 (18.7%) miscarriages (first trimester pregnancy loss of <12 weeks gestation), 18 (8.9%) stillbirths (pregnancy loss after 20 weeks gestation) and 11 (5.4%) cases with intrauterine growth restriction. Maternal pregnancy outcomes were as follows: 8 (3.9%) developed pre-eclampsia, 2 (0.9%) developed eclampsia, 31 (15.3%) developed gestational hypertension and 3 (1.5%) developed gestational diabetes. Women with MCTD and aPL and pulmonary or muscular involvement had worse foetal outcomes compared with those without. Moreover, we report a case of complete congenital heart block (0.45%) and a case of cutaneous neonatal lupus, both born to a mother with positive isolated anti-U1RNP and negative anti-Ro/SSA antibodies. Conclusion In our multicentre cohort, women with MCTD had a live birth rate of 72%. While the true frequency of heart block associated with anti-U1RNP remains to be determined, this study might raise the consideration of echocardiographic surveillance in this setting. Pregnancy counselling should be considered in women with MCTD. [ABSTRACT FROM AUTHOR]

Aims: To describe aetiologies and temporal trends in young patients with atrioventricular block (AVB).Methods and Results: We identified all patients in Denmark, receiving their first pacemaker because of AVB before the age of 50 years between 1996 and 2015. Medical records were reviewed and clinical information and diagnostic work-up results were obtained to evaluate the aetiology. We used Poisson regression testing for temporal trends. One thousand and twenty-seven patients were identified, median age at time of implantation was 38 (interquartile range 25-45) years, 584 (56.9%) were male. The aetiologies were complications to cardiac surgery [n = 157 (15.3%)], congenital AVB [n = 93 (9.0%)], cardioinhibitory reflex [n = 52 (5.0%)], congenital heart disease [n = 43 (4.2%)], complication to radiofrequency ablation [n = 35 (3.4%)], cardiomyopathy [n = 31 (3.0%)], endocarditis [n = 18 (1.7%)], muscular dystrophy [n = 14 (1.4%)], ischaemic heart disease [n = 14 (1.4%)], sarcoidosis [n = 11 (1.1%)], borreliosis [n = 9 (0.9%)], hereditary [n = 6 (0.6%)], side-effect to antiarrhythmics [n = 6 (0.6%)], planned His-ablation [n = 5 (0.5%)], complication to alcohol septal ablation [n = 5 (0.5%)], and other known aetiologies [n = 11 (1.1%)]. The aetiology remained unknown in 517 (50.3%) cases. While the number of patients with unknown aetiology increased during the study period (P < 0.001), we observed no significant change in the number of patients with identified aetiology (P = 0.35).Conclusion: In a nationwide cohort, the aetiology of AVB was identified in only half the patients younger than 50 years referred for first-time pacemaker implantation. The number of patients with unknown aetiology increased during the study period. These findings indicate need for better insight into aetiologies of AVB and improved diagnostic work-up guidelines. [ABSTRACT FROM AUTHOR]

Objective: The aims of this study are to determine the incidence of congenital heart block (CHB) in the Japanese population and identify maternal factors predicting fetal CHB in anti-Ro/SSA antibody positive pregnancy. Methods: A retrospective study was performed using 52,147 clinical records of pregnancies followed in a single center. For 183 anti-Ro/SSA antibody-positive women, anti-Ro52 and Ro60 antibodies were measured, and the odds of CHB in relation to maternal clinical features were calculated by multivariate analysis. The receiver-operating characteristic (ROC) curves for predicting CHB were constructed for the titers of anti-Ro/SSA, anti-Ro52 and anti-Ro60 antibodies. Results: Fetal CHB occurred in two pregnancies among those without known risks such as positive anti-Ro/SSA antibody or previous CHB-affected pregnancy, suggesting an incidence similar to that in Caucasian populations. As for the anti-Ro/SSA antibody positive pregnancies, the titers of anti-Ro/SSA, anti-Ro52 and anti-Ro60 antibodies were independent risk factors for fetal CHB and the use of corticosteroids before 18 gestational weeks was an independent protective factor. The area under the ROC was 0.84, 0.73 and 0.74 for anti-Ro52, anti-Ro60 and anti-Ro/SSA antibodies, respectively. Conclusion: CHB occurred in two among approximately 50,000 pregnancies without known risks such as positive anti-Ro/SSA antibody or previous delivery of CHB-affected babies. Measurement of anti-Ro52 antibody levels may be helpful in extracting a risk group of delivering CHB infants in the anti-Ro/SSA antibody positive pregnancy. [ABSTRACT FROM AUTHOR]

Objectives. Congenital heart block (CHB) develops in 1-2% of anti-Ro/SSA-positive pregnancies and has a recurrence rate of 12-20%, which indicates that factors other than maternal autoantibodies are crucial for CHB to occur. Here, we aimed to evaluate the influence of factors previously associated with CHB on the occurrence of milder forms of fetal cardiac conduction disturbances, shown to occur in up to 30% of anti-Ro/SSA-positive pregnancies, and on neonatal outcome in a large cohort of prospectively followed pregnancies. Methods. The association of maternal age, season of the year and history of atrioventricular block (AVB) with the development of fetal Doppler and neonatal ECG conduction disturbances was evaluated in 212 anti-Ro52/SSA-positive singleton pregnancies. Results. Maternal age was significantly higher in AVB II-III pregnancies but was not correlated with fetal AV time intervals in fetuses without signs of AVB II-III. AV time intervals of fetuses surveilled during the winter were significantly longer than those of fetuses surveilled during the summer. Fetal AV time intervals in consecutive pregnancies from the same women were significantly correlated. A history of AVB II-III was associated with significantly longer AV time intervals, and AVB I-III was observed at birth in 38% of babies born after a sibling with abnormal fetal AV conduction. Conclusion. Our study shows that AV time intervals in anti-Ro/SSA antibody-exposed fetuses during the CHB risk period are influenced by the season of the year, and reveals that the recurrence of conduction disturbances in antibody-exposed fetuses is higher than previously reported when milder forms are taken into account. [ABSTRACT FROM AUTHOR]

Objective. Recent studies have suggested that prenatal exposure to HCQ reduces the risk of cardiac neonatal lupus. The aim of this study is to assess if maternal intake of antimalarials (AMs) throughout pregnancy lowered the risk of cardiac and non-cardiac neonatal lupus. Methods. Consecutive children seen between 1 January 1984 to 1 October 2013 born to women with a CTD and positive anti-Ro and/or anti-La antibodies were eligible for this single-centre retrospective cohort study. A total of 315 individuals were screened and 268 participants were included. Exposure to AMs was defined as HCQ or chloroquine throughout pregnancy. Outcomes were cardiac and non-cardiac neonatal lupus. Frequentist and Bayesian analyses were performed. We hypothesized that prenatal AM exposure would decrease the risk of cardiac but not non-cardiac neonatal lupus. Results. A total of 268 pregnancies were included; 73 were exposed to AMs throughout pregnancy. Ninety-nine children developed neonatal lupus, 117 remained unaffected and 52 children did not develop cardiac neonatal lupus but could not be categorized as unaffected since their full non-cardiac neonatal lupus status was unknown. Logistic regression suggested a protective effect of AM on cardiac neonatal lupus, but results were not statistically significant [odds ratio (OR) 0.21; P = 0.07]. Bayesian analysis showed that the probability of obtaining a protective effect (OR<1.0) for cardiac neonatal lupus was significant (98.7%). The effect of AMs on non-cardiac neonatal lupus was not significant (OR 0.78; P = 0.21). Conclusion. In this large single-centre cohort study, exposure to AMs throughout pregnancy was asso- ciated with a decreased probability of developing cardiac but not non-cardiac neonatal lupus. [ABSTRACT FROM AUTHOR]

Congenital heart block (CHB) is a potentially lethal condition characterized by a third-degree atrioventricular block (AVB). Despite anti-Ro52 antibodies being detected in nearly 90% of mothers of affected children, CHB occurs in only 1-2% of anti-Ro/Sjögren's-syndrome-related antigen A (SSA) autoantibody-positive pregnancies. Maternal antibodies have been suggested to bind molecules crucial to fetal cardiac function; however, it remains unknown whether a single antibody profile associates with CHB or whether several specificities and cross-reactive targets exist. Here, we aimed to define further the reactivity profile of CHB-associated antibodies towards Ro52p200 (amino acid 200-239). We first analysed reactivity of a monoclonal anti-Ro52 antibody shown to induce AVB in rats (7.8C7) and of sera from anti-Ro52p200 antibody-positive mothers of children with CHB towards a panel of modified Ro52p200 peptides, and subsequently evaluated their potential to induce AVB in rats upon transfer during gestation. We observed that CHB maternal sera displayed a homogeneous reactivity profile targeting preferentially the C-terminal part of Ro52p200, in contrast to 7.8C7 that specifically bound the p200 N-terminal end. In particular, amino acid D233 appeared crucial to maternal antibody reactivity towards p200. Despite low to absent reactivity towards rat p200 and different binding profiles towards mutated rat peptides indicating recognition of different epitopes within Ro52p200, immunoglobulin (Ig)G purified from two mothers of children with CHB could induce AVB in rats. Our findings support the hypothesis that several fine antibody specificities and cross-targets may exist and contribute to CHB development in anti-Ro52 antibody-positive pregnancies. [ABSTRACT FROM AUTHOR]

Objective: To determine the maternal predictive factors for fetal congenital heart block (CHB) in pregnancy in mothers positive for anti-SS-A antibodies. Methods: The Research Team for Surveillance of Autoantibody-Exposed Fetuses and Treatment of Neonatal Lupus Erythematosus, the Research Program of the Japan Ministry of Health, Labor and Welfare, performed a national survey on pregnancy of mothers positive for anti-SS-A antibodies. We analyzed 635 pregnant mothers who tested positive for anti-SS-A antibodies before conception but had no previous history of fetal CHB. We performed univariate and multivariate analysis (models 1, 2, and 3 using different set of independent variables) investigated the relation between risk of fetal CHB and maternal clinical features. Results: Of the 635 pregnant mothers, fetal CHB was detected in 16. Univariate analysis showed that fetal CHB associated with use of corticosteroids before conception (OR 3.72, p=0.04), and negatively with use of corticosteroids (equivalent doses of prednisolone (PSL), at -10 mg/day) after conception before 16-week gestation (OR 0.17, p=0.03). In multivariate analysis, model 1 identified the use of corticosteroids before conception (OR 4.28, p=0.04) and high titer of anti-SS-A antibodies (OR 3.58, p=0.02) as independent and significant risk factors, and model 3 identified use of corticosteroids (equivalent doses of PSL, at -10 mg/day) after conception before 16-week gestation as independent protective factor against the development of fetal CHB (OR 0.16, p=0.03). Other maternal clinical features did not influence the development of fetal CHB. Conclusion: The results identified high titers of anti-SS-A antibodies and use of corticosteroids before conception as independent risk factors, and use of corticosteroids (equivalent doses of PSL, at -10 mg/day) after conception before 16-week gestation as an independent protective factor for fetal CHB. [ABSTRACT FROM AUTHOR]

Aims We aim to engineer a computational model of propagation during normal sinus rhythm in the foetal human heart, by modifying models for adult cardiac tissue to match foetal electrocardiogram (fECG) characteristics. The model will be partially validated by fECG data, and applied to explore possible mechanisms of arrhythmogenesis in the foetal heart. Methods and results Foetal electrocardiograms have been recorded during pregnancy, with P- and T-waves, and the QRS complex, identified by averaging and signal processing. Intervals of the fECG are extracted and used to modify currently available human adult cardiomyocyte models. RR intervals inform models of the pacemaking cells by constraining their rate, the QT interval and its rate dependence constrain models of ventricular cells, and the width of the P-wave, the QR and PR intervals constrain propagation times, conduction velocities, and intercellular coupling. These cell models are coupled into a one-dimensional (1D) model of propagation during normal sinus rhythm in the human foetal heart. We constructed a modular, heterogeneous 1D model for propagation in the foetal heart, and predicted the effects of reduction in L-type Ca++ current. These include bradycardia and atrioventricular conduction blocks. These may account quantitatively for congenital heart block produced by positive IgG antibodies. Conclusion The fECG can be interpreted mechanistically and quantitatively by using a simple computational model for propagation. After further validation, by clinical recordings of the fECG and the electrophysiological experiments on foetal cardiac cells and tissues, the model may be used to predict the effects of maternally administered pharmaceuticals on the fECG. [ABSTRACT FROM PUBLISHER]

Maternal autoantibodies to the p200-epitope of Ro52 have been suggested to correlate with development of congenital heart block. The aim of the present study was to evaluate the clinical relevance and predictive value of p200-antibodies in high-risk pregnancies. Sera from 515 Finnish, Swedish and American women were included in the study. Sera originated from 202 mothers with an infant affected by second- or third-degree atrioventricular block (AVB), 177 mothers with rheumatic disease having infants with normal heart rate and female blood donors ( n = 136). A novel serological assay for Ro52 p200-antibodies with intra- and inter-assay variability of 3% and 3·8% respectively was developed. Mothers of children affected by AVB II-III had significantly higher p200-antibody levels than mothers with rheumatic disease having children with normal heart rate ( P < 0·001). In the Swedish cohort, a distinction between foetuses with normal conduction, AVB I, AVB II and III was possible. A significant difference in anti-p200 levels between AVB I and AVB II-III groups compared with foetuses with normal conduction ( P < 0·05 and P < 0·01) was observed. Using p200-antibodies as a second step analysis in Ro52-positive pregnancies increased the positive predictive value for foetal cardiac involvement (AVB I, II or III) from 0·39 (0·27–0·51) to 0·53 (0·37–0·68). In conclusion, Ro52 p200-antibodies may occur in women with unaffected children, but levels are significantly higher in mothers of children with congenital heart block and are suggested as a relevant marker in evaluating the risk for foetal AV block. [ABSTRACT FROM AUTHOR]

Opsonization of apoptotic cardiocytes by maternal anti-Ro/SSA and anti-La/SSB antibodies contributes to tissue injury in the neonatal lupus syndrome. The objective of the current study was to quantify the surface membrane expression of Ro/La components during different phases of apoptosis and map the Ro/La apotopes (epitopes expressed on apoptotic cells) bound by cognate antibodies. Multi-parameter flow cytometry was used to define early and late apoptotic populations and their respective binding by monospecific anti-Ro and anti-La IgGs. Anti-Ro60 bound specifically to early apoptotic Jurkat cells and remained accessible on the cell surface throughout early and late apoptosis. In contrast, anti-La bound exclusively to late apoptotic cells in experiments controlled for non-specific membrane leakage of IgG. Ro52 was not accessible for antibody binding on either apoptotic population. The immunodominant NH2-terminal and RNA recognition motif (RRM) epitopes of La were expressed as apotopes on late apoptotic cells, confirming recent in vivo findings. An immunodominant internal epitope of Ro60 that contains the RRM, and is recognized by a majority of sera from mothers of children with congenital heart block (CHB) and patients with primary Sjögren's syndrome, was also accessible as an apotope on early apoptotic cells. The distinct temporal expression of the immunodominant Ro60 and La apotopes indicates that these intracellular autoantigens translocate independently to the cell surface, and supports a model in which maternal antibody populations against both Ro60 and La apotopes act in an additive fashion to increase the risk of tissue damage in CHB. [ABSTRACT FROM AUTHOR]

Aims: We aimed to assess the evolution of left ventricular (LV) systolic function in children with right ventricular apical (RVA) pacing for isolated congenital heart block (ICHB) and to identify possible predictors of LV function deterioration. Right ventricular apical pacing can be detrimental to LV function in a significant number of adults. Effects in children are still controversial. [ABSTRACT FROM PUBLISHER]

Mothers who have anti-SS-A/Ro and anti-SS-B/La antibodies have a greater risk of bearing infants with neonatal lupus erythematosus (NLE). However, most mothers with anti-SS-A/Ro and anti-SS-B/La antibodies give birth to infants with no evidence of NLE. We studied mothers who had the combination of clinical evidence of connective tissue disorder, positive antinuclear antibody and positive anti-SS-A/Ro and/or anti-SS-B/La antibodies. We analysed SS-A/Ro and SS-B/La antibody responses to recombinant 60-, 52- and 50-kDa proteins in eight mothers of NLE infants and 19 mothers whose children did not have NLE. Molecular analysis of the anti-SS-A/Ro and anti-SS-B/La antibodies was carried out by enzyme-linked immunosorbent assay using recombinant 60-, 52- and 50-kDa proteins. The mothers of children with cutaneous NLE were all positive for a high titre of 50-kDa protein. Mothers of children with NLE with complete heart block (CHB) were positive for 52- and 60-kDa proteins. We conjecture that anti-SS-B/La antibody influences the development of cutaneous NLE, and that anti-SS-A/Ro antibody influences the development of NLE with CHB. [ABSTRACT FROM AUTHOR]

The clinical course in 70 adult patients with isolated congenital complete heart block is described. The mean age at follow-up was 31 years. Twenty-seven patients were diagnosed before one year of age. Seventy per cent of patients below 30 years of age and 29%ents above 30 years were symptom free. One group of 48 patients was prospectively followed for 12 years. During this time nine were paced and two died. No reliable indicators of bad prognosis were found. Aeliologically, congenital complete heart block is probably a mixed group and the difficulty of distinguishing congenital from acquired block is discussed. [ABSTRACT FROM PUBLISHER]

To study the maternal immunogenetics in congenital heart block (CHB), 31 mothers of affected children were HLA typed for class I and II antigens, and the results were compared with the corresponding HLA types in 900 healthy controls, in 45 mothers with systemic lupus erythematosus (SLE) and in 21 mothers with primary SS who had healthy children. An enzyme-linked immunosorbent assay was used to study the autoantibody responses to the recombinant 52 and 60 kDa SS-A/Ro, and 48 kDa SS-B/La proteins, and to the affinity-purified SS-A/Ro and SS-B/La antigens. Mothers of children with CHB had HLA B8 and DR3 significantly more often than healthy controls [71 20%; relative risk (RR) 9.8, <0.00001 and 74 23% RR 9.8, <0.0001, respectively]. HLA B35 was protective (RR 0.1, = 0.0029). Compared to controls with SLE, mothers of children with CHB were more often HLA DR3 and DQ2 positive (RR 4.1, = 0.0057 and RR 3.1, = 0.031, respectively), and compared to controls with primary SS less often HLA B15 positive (RR 0.1, =0.010). In general, the HLA antigen profile in mothers of children with CHB was more closely related to primary SS than to SLE. Levels of antibodies to all three SS-A/Ro antigens were significantly higher in mothers of children with CHB than in controls with SLE and primary SS ( = 0.0001–-0.0014). With regard to SS-B/La, the autoantibody responses were similar ( = 0.32-0.66). HLA B8, DR3, DQ2 and heterozygosity for DQ1/DQ2 were strongly associated with all three assays for antibodies to SS-A/Ro ( =0.0001–0.018). The corresponding associations with antibodies to SS7-B/La were weaker ( = 0.0076–1.0). The common immunogenetic background of the mother for having a child with CHB is the presence of HLA antigens B8, DR3 and DQ2 associated with high levels of antibodies to SS7-A/Ro. Mothers of children with CHB are genetically more closely related to patients with primary SS than to patients with SLE. [ABSTRACT FROM PUBLISHER]

Mesothelioma of atrioventricular nodes may cause congenital heart block and diagnosis is usually confirmed at postmortem. Awareness of the possibility of the development of this tumour and selective coronary arteriography may help to diagnose this in life. [ABSTRACT FROM PUBLISHER]