Subclinical maternal autoimmune disease leading to congenital high degree atrioventricular block: Case report and review of the literature.

Maternal autoimmune disease is the most common cause of congenital heart block (CHB), a rare illness characterized by fibrosis and calcification of the fetal atrioventricular (AV) node due to maternal autoantibodies anti-SSA/Ro and anti-SSB/La. We report the full autopsy and clinical information on a female neonate with high degree AV block and calcification in the AV node, atrial approaches to the AV node, and both right and left bundle branches, born to a 27-year-old female with subclinical autoimmune disease.

Cohort study of congenital complete heart block among preterm neonates: a single-center experience over a 15-year period.

Congenital complete heart block (CCHB) is a very rare condition, with high risk of mortality. Prematurity is associated with immaturity of the cardiovascular system. Morbidity related to CCHB and prematurity has never been described. We describe a tertiary perinatal center experience over a 15-year period on CCHB management and complications in preterm infants. This is a single-center observational cohort study. All neonates admitted to neonatal intensive care unit with a diagnosis of isolated CCHB between January 2006 and January 2021 were identified. All preterm neonates (< 37 weeks) were compared with a control cohort of term neonates (≥ 37 weeks). Antenatal data, complications of prematurity, medical, and surgical management of CCHB were recorded. Twenty-four neonates with isolated CCHB (16 preterm and 8 term) were born during the study period, including 5 very preterm (< 32 weeks) and 11 preterm (32 to 37 weeks). All very preterm were born via emergency caesarian section without antenatal steroid administration. They had multiple severe morbidities including chronic lung disease, necrotizing enterocolitis, grades 3-4 intraventricular hemorrhage, cystic periventricular leukomalacia, and longer periods of mechanical and non-invasive ventilatory support than preterm. Thirteen out of sixteen preterm infants had permanent pacemakers inserted, compared to 1/8 for term newborns. All babies born before 35-week gestation were either paced or died.Conclusion: Premature neonates with CCHB have high risk of mortality and morbidity especially if undiagnosed and born by unnecessary emergency caesarian section without antenatal steroids. Prematurity below 35 weeks may be associated with death or pacemaker insertion. This supports better antenatal screening to avoid induced prematurity. What is Known: • Congenital complete heart block is a very rare condition associated with high morbidity and mortality. • Antenatal risk factors for poor outcome include fetal hydrops, low ventricular rate (HR <55 beats per minute), and congenital heart defect. What is New: • Infants born <32 weeks with CCHB had no antenatal steroid administration, and sustained high burden of morbidity (chronic lung disease, intraventricular hemorrhage, and cystic periventricular leukomalacia). • Birth <35 weeks is strongly associated with requiring pacing prior to discharge or death.

Pulmonary hypertension associated with congenital heart block and neonatal lupus syndrome: A series of four cases.

OBJECTIVE: Neonatal lupus syndrome has multisystemic manifestations among which pulmonary involvement has been rarely reported. We describe the clinical presentation, management, and outcome of a series of four neonates who developed reversible pulmonary hypertension associated with auto-immune congenital complete heart block. METHOD: Data from the French registry of neonatal lupus syndrome were retrospectively reviewed. RESULTS: Between 2000 and March 2020, 231 children were included in the French registry, four/73 followed in our institution developed pulmonary hypertension. Diagnosis was suspected on transthoracic echocardiography at a median age of 42 days [range 10-58], and confirmed by right heart catheterization in all; 2 of them where paced at time of diagnosis and 2 were not. All had some degree of hypoxemia and respiratory distress. Hypoxemia was always reversible under O2 et NO. Lung CT demonstrated ground glass anomalies in all. One patient had a lung biopsy consistent with pulmonary hypertension secondary to lung disease. Management included immunosuppressive therapy in 3 associated with sildenafil in 2. Pulmonary hypertension resolved in all at a median age of 4 weeks [range 3-6] after treatment initiation and after one year for the one child who did not receive specific treatment. CONCLUSION: Clinical, hemodynamical, imaging and histological findings advocate for pulmonary hypertension associated with respiratory disease as a rare manifestation of neonatal lupus syndrome.

Interferons and innate immune activation in autoimmune congenital heart block.

Autoimmune congenital heart block (CHB) may develop in foetuses of women carrying anti-Ro/SSA and La/SSB autoantibodies and is characterized by disruption of signal conduction at the atrioventricular (AV) node, resulting in partial or complete AV block. If not fatal in utero, complete CHB typically requires lifelong cardiac pacing. No treatment has so far been unequivocally demonstrated to prevent or treat autoimmune CHB, and the relatively low incidence (1%-5%) and recurrence (12%-16%) rates of second/third-degree AV block add to the complexity of managing pregnancies in women with anti-Ro/La antibodies. Altogether, a better understanding of events leading to development of autoimmune CHB is needed to improve surveillance and treatment strategies. In the past decade, studies have started to look beyond the role of maternal autoantibodies in disease pathogenesis to assess other contributing factors such as foetal genetics and, more recently, immune responses in foetuses and neonates of anti-Ro/La antibody-positive women. In this review, we provide an update on the epidemiology, clinical presentation and current treatment approaches of autoimmune CHB, summarize the previously proposed pathogenic mechanisms implicating maternal autoantibodies, and discuss the recent findings of type I interferon (IFN) and innate immune activation in foetuses with autoimmune CHB and in neonates of anti-Ro/La antibody-positive mothers, and how these may contribute to autoimmune CHB pathogenesis.

A missense mutation of ErbB2 produces a novel mouse model of stillbirth associated with a cardiac abnormality but lacking abnormalities of placental structure.

BACKGROUND: In humans, stillbirth describes the death of a fetus before birth after 28 weeks gestation, and accounts for approximately 2.6 million deaths worldwide annually. In high-income countries, up to half of stillbirths have an unknown cause and are described as "unexplained stillbirths"; this lack of understanding impairs efforts to prevent stillbirth. There are also few animal models of stillbirth, but those that have been described usually have significant placental abnormalities. This study describes a novel mutant murine model of fetal death with atrial conduction block due to an ErbB2 missense mutation which is not associated with abnormal placental morphology. METHODS: Phenotypic characterisation and histological analysis of the mutant mouse model was conducted. The mRNA distribution of the early cardiomyocyte marker Nkx2-5 was assessed via in situ hybridisation. Cardiac structure was quantified and cellular morphology evaluated by electron microscopy. Immunostaining was employed to quantify placental structure and cell characteristics on matched heterozygous and homozygous mutant placental samples. RESULTS: There were no structural abnormalities observed in hearts of mutant embryos. Comparable Nkx2-5 expression was observed in hearts of mutants and controls, suggesting normal cardiac specification. Additionally, there was no significant difference in the weight, placenta dimensions, giant cell characteristics, labyrinth tissue composition, levels of apoptosis, proliferation or vascularisation between placentas of homozygous mutant mice and controls. CONCLUSION: Embryonic lethality in the ErbB2 homozygous mutant mouse cannot be attributed to placental pathology. As such, we conclude the ErbB2M802R mutant is a model of stillbirth with a non-placental cause of death. The mechanism of the atrial block resulting from ErbB2 mutation and its role in embryonic death is still unclear. Studying this mutant mouse model could identify candidate genes involved in stillbirth associated with structural or functional cardiac defects.

Congenital complete atrioventricular heart block in a pregnant woman with sjögren syndrome: prenatal care follow-up and the challenge of intrauterine treatment / Bloqueio atrioventricular completo congênito em uma mulher grávida com síndrome de Sjögren: seguimento pré-natal e desafio do tratamento intrauterino

Abstract The present report describes a case of complete atrioventricular block (CAVB) diagnosed at 25 weeks of gestation in a pregnant woman with Sjögren's syndrome and positive anti-Ro/SSA antibodies. Fluorinated steroids (dexamethasone and betamethasone) and terbuline were used to increase the fetal heart rate, but the fetal heart block was not reversible, and the administration of drugs was discontinued due to maternal collateral effects. Follow-up fetal echocardiograms were performed, and the fetus evolved with pericardial effusion, presence of fibroelastosis in the right ventricle, and ventricular dysfunction. Interruption of pregnancy by cesarean section was indicated at 34 weeks of gestation, and a cardiac pacemaker was implanted in the male newborn immediately after birth. Therapy for fetuses with CAVB is controversial mainly regarding the use or not of corticosteroids; however, monitoring of the atrioventricular interval by fetal echocardiography should be performed in fetuses from pregnant women with positive autoantibodies anti-Ro/SSA and/or anti-La/SSB to prevent the progression to CAVB.

Resumo Este relato descreve um caso de bloqueio atrioventricular completo (BAVC) diagnosticado com 25 semanas de gestação em uma mulher com síndrome de Sjögren e anticorpos anti-Ro/SSA positivos. Esteroides fluoretados (dexametasona e betametasona) e terbulina foram utilizados para aumentar a frequência cardíaca fetal, mas o bloqueio cardíaco fetal não foi reversível, e a administração dos medicamentos foi interrompida devido a efeitos colaterais maternos. Ecocardiogramas fetais de acompanhamento foram realizados, e o feto evoluiu com derrame pericárdico, presença de fibroelastose no ventrículo direito, e disfunção ventricular. A interrupção da gravidez por cesariana foi indicada com 34 semanas, e um marca-passo cardíaco foi implantado no recém-nascido do sexo masculino imediatamente após o nascimento. A terapia para fetos com BAVC é controversa, principalmente no que diz respeito ao uso ou não de corticosteroides; no entanto, o monitoramento do intervalo atrioventricular pela ecocardiografia fetal deve ser feito em fetos de mulheres grávidas com autoanticorpos positivos anti-Ro/SSA e/ou anti-La/SSB para impedir a progressão para o BAVC.

Pacemaker Implantation in Neonates and Infants: Favorable Outcomes with Epicardial Pacing Systems.

The implantation of pacemakers (PM) in neonates and infants requires particular consideration of small body size, marked body growth potential, and the decades of future pacing therapy to be expected. The aim of this study is to quantify the complications of implantation and outcome occurring at our center and to compare these with other centers. Retrospective analysis of 52 consecutive patients undergoing PM implantation at a single tertiary care center within the first year of life. PMs were implanted at a median age of 3 months (range 0-10 months). Structural heart defects were present in 44 of 52 patients. During a median follow-up time of 40.4 months (range 0.1-114 months), measurements for sensing, pacing thresholds, and lead impedance remained stable. No adverse pacing effect was observed in left ventricular function or dimensions over time. There were 20 reoperations in 13 patients at a median time of 4.7 years (range 0.05-8.2 years) after implantation, for end of battery life (n = 10), lead dysfunction (n = 3), device dislocation (n = 3), infection (n = 3), and diaphragmatic paresis (n = 1). No PM-related mortality occurred. Epicardial pacemaker implantation in neonates and infants is an invasive but safe and effective procedure with a relatively low risk of complications. Our current implantation technique and the use of bipolar steroid-eluting electrodes, which we prefer to implant on the left ventricular apex, lead to favorable long-term results.

Long-term Follow-up of Epicardial Pacing and Left Ventricular Dysfunction in Children With Congenital Heart Block.

BACKGROUND: Patients with congenital complete atrioventricular block often require lifelong pacemaker therapy, which has a risk of left ventricular (LV) dysfunction. The aim of our study was to determine the long-term effects of epicardial pacing on LV function and dyssynchrony in children with congenital heart block. METHODS: We conducted a retrospective study at a single tertiary center in which 34 pediatric patients with isolated congenital complete heart block who underwent epicardial pacemaker implantation from 1987 to 2016 were enrolled. RESULTS: Median age during pacemaker insertion was 2.5 years (range, 0-16.7 years) and the median follow-up duration was 12.3 years. The initial pacing sites were the right ventricle (RV) free wall for 10 patients, RV apex for 16, and LV apex for eight. LV dysfunction developed in 7 patients, of whom 4 underwent lead relocation to the RV apex (n = 2) and cardiac resynchronization therapy upgrade (n = 2). RV free-wall pacing had a significantly higher risk of LV dysfunction than either LV or RV apical pacing (odds ratio 52.5; P = .003; 95% confidence interval 3.9-700). All 4 patients who underwent lead repositioning showed improvement of LV function (median ejection fraction, 24%-62.7%). CONCLUSIONS: Our study suggests that RV free-wall pacing may be a significant risk factor for LV dysfunction. Pacemaker-induced LV dysfunction was improved via lead relocation to the RV apex or cardiac resynchronization therapy upgrade. Future studies with a larger sample size and longer-term follow-up are required to confirm our results.

Minimally invasive technique of placing a dual chamber permanent pacemaker in children.

OBJECTIVE: To share the experience of a minimally invasive technique in the implantation of a dual chamber permanent pacemaker in paediatric population. METHODS: The retrospective study was conducted at Aga Khan University Hospital, Karachi, and comprised data of patients aged up to 16 years who underwent epicardial dual chamber permanent pacemaker insertion via xiphisternal incision between April 2011 and August 2016. Demographic data included age, weight and gender of the patient. Indications for pacemaker insertion, electrocardiography findings, concomitant cardiac procedures and procedural complications were reviewed. Pacemaker thresholds and impedance at the time of implantation and throughout the course of follow-up were extracted from the clinical data. RESULTS: Of the 10 patients, 5(50%) were males and 5(50%)were females. The overall mean age was 3.4}3.8 years (range: 1 month - 13 years). The mean weight at the time of operation was 11.4}6.8 kg (range: 4.3-27kg). Indications for permanent pacemaker insertion included postoperative advanced or complete atrioventricular block in 7(70%) and complete congenital heart block in 3(30%). There was no reported morbidity. CONCLUSIONS: Dual chamber permanent pacemaker insertion via xiphisternal incision was found to be of benefit to the patients and the surgeons alike.

Siglec-1 Macrophages and the Contribution of IFN to the Development of Autoimmune Congenital Heart Block.

Given that diseases associated with anti-SSA/Ro autoantibodies, such as systemic lupus erythematosus and Sjögren syndrome, are linked with an upregulation of IFN and type I IFN-stimulated genes, including sialic acid-binding Ig-like lectin 1 (Siglec-1), a receptor on monocytes/macrophages, recent attention has focused on a potential role for IFN and IFN-stimulated genes in the pathogenesis of congenital heart block (CHB). Accordingly, three approaches were leveraged to address the association of IFN, IFN-stimulated genes, and the phenotype of macrophages in affected fetal cardiac tissue: 1) cultured healthy human macrophages transfected with hY3, an anti-SSA/Ro-associated ssRNA, 2) RNA isolated from freshly sorted human leukocytes/macrophages after Langendorff perfusion of three fetal hearts dying with CHB and three healthy gestational age-matched hearts, and 3) autopsy tissue from three additional human CHB hearts and one healthy heart. TLR ligation of macrophages with hY3 led to the upregulation of a panel of IFN transcripts, including SIGLEC1, a result corroborated using quantitative PCR. Using independent and agnostic bioinformatics approaches, CD45+CD11c+ and CD45+CD11c- human leukocytes flow sorted from the CHB hearts highly expressed type I IFN response genes inclusive of SIGLEC1. Furthermore, Siglec-1 expression was identified in the septal region of several affected fetal hearts. These data now provide a link between IFN, IFN-stimulated genes, and the inflammatory and possibly fibrosing components of CHB, positioning Siglec-1-positive macrophages as integral to the process.

Posterior Spinal Fusion in a Scoliotic Patient With Congenital Heart Block Treated With Pacemaker: An Intraoperative Technical Difficulty.

STUDY DESIGN: Case report. OBJECTIVE: To describe the technical difficulties on performing posterior spinal fusion (PSF) on a pacemaker-dependent patient with complete congenital heart block and right thoracic scoliosis. SUMMARY OF BACKGROUND DATA: Congenital complete heart block requires pacemaker implantation at birth through thoracotomy, which can result in scoliosis. Corrective surgery in this patient was challenging. Height gain after corrective surgery may potentially cause lead dislodgement. The usage of monopolar electrocautery may interfere with the function of the implanted cardiac device. METHODS: A 17-year-old boy was referred to our institution for the treatment of right thoracic scoliosis of 70°. He had underlying complete congenital heart block secondary to maternal systemic lupus erythematosus. Pacemaker was implanted through thoracotomy since birth and later changed for four times. PSF was performed by two attending surgeons with a temporary pacing inserted before the surgery. The monopolar electrocautery device was used throughout the surgery. RESULTS: The PSF was successfully performed without any technical issues and complications. Postoperatively, his permanent pacemaker was functioning normally. Three days later, he was recovering well and was discharged home from hospital. CONCLUSION: This case indicates that PSF can be performed successfully with thoughtful anticipation of technical difficulties on a pacemaker-dependent patient with underlying congenital heart block. LEVEL OF EVIDENCE: 5.

Epicardial permanent pacemaker implantation in the retrosternal space of a 2.3-kg infant.

Permanent pacemaker implantation in small infants can be challenging because of patient size and expected somatic growth. In our case, we used the retrosternal space as a generator pocket for an extremely low-birth-weight premature baby with autoantibody-associated congenital heart block born to a systemic lupus erythematosus mother.

Permanent pacemaker implantation in complete congenital fetal atrioventricular (AV) block: a case report / Implantación de marcapasos permanente en bloqueo atrioventricular (AV) fetal congénito completo: reporte de caso

Abstract: One of the most common pathologies attributed to lupus neonatal refers to atrioventricular (AV) congenital block, which diagnosis can be made between 16 and 30 weeks of gestation due to persistent fetal bradycardia. The development of this disease is mostly related to maternal anti-Ro/SSA and anti-Smith autoantibodies. Currently, there are a number of alternatives for prenatal and postnatal treatment, with some controversy about their viability. The placement of a permanent pacemaker is presented as one of the most appropriate procedures currently, even with the risks awarded. This case report describes the placement of a permanent pacemaker to a two-month-old newborn with high maternal contents of anti-Ro/SSA and anti-Smith nuclear autoantibodies, with a favorable outcome.(AU)

Resumen: Una de las patologías más comunes atribuidas al lupus neonatal se refiere al bloqueo congénito atrioventricular (AV), diagnóstico que se puede realizar entre 16 y 30 semanas de gestación debido a bradicardia fetal persistente. El desarrollo de esta enfermedad se relaciona principalmente con los anticuerpos anti-Ro/SSA materno y anti-Smith. Actualmente, existen varias alternativas para el tratamiento prenatal y postnatal, con cierta controversia sobre su viabilidad. La colocación de un marcapasos permanente se presenta como uno de los procedimientos más adecuados actualmente, incluso con los riesgos adjudicados. Este relato de caso describe la colocación de un marcapasos permanente en un recién nacido de dos meses con alto contenido materno de autoanticuerpos anti-Ro/SSA y anti-Smith, con un resultado favorable.(AU)

Minimally Invasive Epicardial Pacemaker Implantation in Neonates with Congenital Heart Block / Implante de Marca-Passo Epicárdico por Acesso Minimamente Invasivo em Neonatos com Bloqueio Atrioventricular Congênito

Abstract Background: Few studies have characterized the surgical outcomes following epicardial pacemaker implantation in neonates with congenital complete atrioventricular block (CCAVB). Objective: This study sought to assess the long-term outcomes of a minimally invasive epicardial approach using a subxiphoid access for pacemaker implantation in neonates. Methods: Between July 2002 and February 2015, 16 consecutive neonates underwent epicardial pacemaker implantation due to CCAVB. Among these, 12 (75.0%) had congenital heart defects associated with CCAVB. The patients had a mean age of 4.7 ± 5.3 days and nine (56.3%) were female. Bipolar steroid-eluting epicardial leads were implanted in all patients through a minimally invasive subxiphoid approach and fixed on the diaphragmatic ventricular surface. The pulse generator was placed in an epigastric submuscular position. Results: All procedures were successful, with no perioperative complications or early deaths. Mean operating time was 90.2 ± 16.8 minutes. None of the patients displayed pacing or sensing dysfunction, and all parameters remained stable throughout the follow-up period of 4.1 ± 3.9 years. Three children underwent pulse generator replacement due to normal battery depletion at 4.0, 7.2, and 9.0 years of age without the need of ventricular lead replacement. There were two deaths at 12 and 325 days after pacemaker implantation due to bleeding from thrombolytic use and progressive refractory heart failure, respectively. Conclusion: Epicardial pacemaker implantation through a subxiphoid approach in neonates with CCAVB is technically feasible and associated with excellent surgical outcomes and pacing lead longevity.

Resumo Fundamento: Há poucos estudos caracterizando os desfechos cirúrgicos após implante de marca-passo em neonatos com bloqueio atrioventricular total congênito (BAVTC). Objetivos: Este estudo procurou avaliar os resultados a longo prazo de uma abordagem epicárdica minimamente invasiva com utilização de acesso subxifoide para implante de marca-passo em neonatos. Métodos: Entre julho de 2002 a fevereiro de 2015, 16 neonatos consecutivos foram submetidos a implante de marca-passo epicárdico devido a BAVTC. Entre eles, 12 (75,0%) apresentavam defeitos cardíacos congênitos associados ao BAVTC. Os pacientes tinham uma média de idade de 4,5 ± 5,3 dias e nove (56,3%) eram do sexo feminino. Cabo-eletrodo bipolar revestido com esteroide foi implantado em todos os pacientes através de uma abordagem subxifoide minimamente invasiva e fixado na superfície ventricular diafragmática. O gerador de pulsos foi alojado em uma posição epigástrica submuscular. Resultados: Todos os procedimentos foram realizados com sucesso, sem complicações intraoperatórias ou mortes. O tempo médio de duração das operações foi de 90,2 ± 16,8 minutos. Após seguimento médio de 4,1 ± 3,9 anos e máximo de 12,2 anos, não foram observadas complicações de loja do gerador de pulsos, aumento crônico do limiar de comando, fratura de cabo-eletrodo ou outros problemas relacionados ao sistema de estimulação cardíaca. Três crianças foram submetidas à troca do gerador de pulsos por depleção normal de bateria aos 4,0, 7,2 e 9,0 anos de idade, sem necessidade de troca do cabo-eletrodo ventricular. Houve duas mortes aos 12 e 325 dias após o implante do marca-passo devido a sangramento decorrente do uso de trombolítico e insuficiência cardíaca refratária progressiva, respectivamente. Conclusões: O implante de marca-passo epicárdico através de abordagem subxifoide em neonatos com BAVTC com alojamento epigástrico do gerador de pulsos é tecnicamente viável e associado a excelentes desfechos cirúrgicos e longevidade do cabo-eletrodo de estimulação.

Minimally Invasive Epicardial Pacemaker Implantation in Neonates with Congenital Heart Block.

BACKGROUND: Few studies have characterized the surgical outcomes following epicardial pacemaker implantation in neonates with congenital complete atrioventricular block (CCAVB). OBJECTIVE: This study sought to assess the long-term outcomes of a minimally invasive epicardial approach using a subxiphoid access for pacemaker implantation in neonates. METHODS: Between July 2002 and February 2015, 16 consecutive neonates underwent epicardial pacemaker implantation due to CCAVB. Among these, 12 (75.0%) had congenital heart defects associated with CCAVB. The patients had a mean age of 4.7 ± 5.3 days and nine (56.3%) were female. Bipolar steroid-eluting epicardial leads were implanted in all patients through a minimally invasive subxiphoid approach and fixed on the diaphragmatic ventricular surface. The pulse generator was placed in an epigastric submuscular position. RESULTS: All procedures were successful, with no perioperative complications or early deaths. Mean operating time was 90.2 ± 16.8 minutes. None of the patients displayed pacing or sensing dysfunction, and all parameters remained stable throughout the follow-up period of 4.1 ± 3.9 years. Three children underwent pulse generator replacement due to normal battery depletion at 4.0, 7.2, and 9.0 years of age without the need of ventricular lead replacement. There were two deaths at 12 and 325 days after pacemaker implantation due to bleeding from thrombolytic use and progressive refractory heart failure, respectively. CONCLUSION: Epicardial pacemaker implantation through a subxiphoid approach in neonates with CCAVB is technically feasible and associated with excellent surgical outcomes and pacing lead longevity.

Cardiac fibroblast transcriptome analyses support a role for interferogenic, profibrotic, and inflammatory genes in anti-SSA/Ro-associated congenital heart block.

The signature lesion of SSA/Ro autoantibody-associated congenital heart block (CHB) is fibrosis and a macrophage infiltrate, supporting an experimental focus on cues influencing the fibroblast component. The transcriptomes of human fetal cardiac fibroblasts were analyzed using two complementary approaches. Cardiac injury conditions were simulated in vitro by incubating human fetal cardiac fibroblasts with supernatants from macrophages transfected with the SSA/Ro-associated noncoding Y ssRNA. The top 10 upregulated transcripts in the stimulated fibroblasts reflected a type I interferon (IFN) response [e.g., IFN-induced protein 44-like (IFI44L), of MX dynamin-like GTPase (MX)1, MX2, and radical S-adenosyl methionine domain containing 2 (Rsad2)]. Within the fibrotic pathway, transcript levels of endothelin-1 (EDN1), phosphodiesterase (PDE)4D, chemokine (C-X-C motif) ligand (CXCL)2, and CXCL3 were upregulated, while others, including adenomedullin, RAP guanine nucleotide exchange factor 3 (RAPGEF3), tissue inhibitor of metalloproteinase (TIMP)1, TIMP3, and dual specificity phosphatase 1, were downregulated. Agnostic Database for Annotation, Visualization and Integrated Discovery analysis revealed a significant increase in inflammatory genes, including complement C3A receptor 1 (C3AR1), F2R-like thrombin/trypsin receptor 3, and neutrophil cytosolic factor 2. In addition, stimulated fibroblasts expressed high levels of phospho-MADS box transcription enhancer factor 2 [a substrate of MAPK5 (ERK5)], which was inhibited by BIX-02189, a specific inhibitor of ERK5. Translation to human disease leveraged an unprecedented opportunity to interrogate the transcriptome of fibroblasts freshly isolated and cell sorted without stimulation from a fetal heart with CHB and a matched healthy heart. Consistent with the in vitro data, five IFN response genes were among the top 10 most highly expressed transcripts in CHB fibroblasts. In addition, the expression of matrix-related genes reflected fibrosis. These data support the novel finding that cardiac injury in CHB may occur secondary to abnormal remodeling due in part to upregulation of type 1 IFN response genes.NEW & NOTEWORTHY Congenital heart block is a rare disease of the fetal heart associated with maternal anti-Ro autoantibodies which can result in death and for survivors, lifelong pacing. This study provides in vivo and in vitro transcriptome-support that injury may be mediated by an effect of Type I Interferon on fetal fibroblasts.

Hypoplastic Left Heart Syndrome with Congenital Complete Heart Block.

Congenital complete atrioventricular block (CCAVB) is a rare condition with an incidence of 1 of 20,000 live births. Hypoplastic left heart syndrome (HLHS) occurs more frequently than CCAVB and occurs in 1 of 5000 live births. HLHS in association with CCAVB is exceedingly rare. In this report, we describe a rare case of HLHS and CCAVB diagnosed in utero. Postnatal diagnosis, management and outcome are presented as well as review of the medical literature.

Congenital Complete Heart Block Presenting in Pregnancy: A Case Report.

Congenital complete heart block presenting for the first time in pregnancy is a rare occurrence posing a therapeutic challenge. We present a case of unpaced preexisting congenital complete heart block in pregnancy diagnosed for the first time during routine prenatal care at her early weeks of gestation. Our patient was asymptomatic and haemodynamically stable and was managed conservatively with a multidisciplinary term approach. Intrauterine growth retardation (IUGR) was present and she was delivered by ceasarean section at term for foetal distress with IUGR. Prophylactic temporary pacing was done before surgery and was weaned off in the early postpartum period. When a multidisciplinary approach is used both maternal and neonatal outcome are favorable. We review the literature in an attempt to discuss the therapeutic policy for such patients.