Pathogenesis Of Congenital Heart Block Research Articles

Case Series of Congenital Heart Block: Mothers With anti-Ro Autoantibodies and the Risks to Their Offspring

Introduction: Cardiac manifestation of congenital heart block (CHB) in neonates following maternal anti-Ro and anti-La autoantibodies is a serious complication of neonatal lupus with a prevalence of 1: 22000 live birth and is associated with high morbidity and mortality. Disturbance of calcium homeostasis which leads to electrical conduction abnormality and eventually fibrosis of the heart tissue is the well-known pathogenesis of CHB. Most of the babies with CHB ended up with third-degree heart block and need a pacemaker as it is an irreversible injury. Case series: Here, we reported four case series of neonatal lupus with cardiac manifestation in mothers with positive anti-Ro or anti-La which have been detected during pregnancy within 24 to 32 weeks of gestation. All four cases of newborns ended up with third-degree heart block which required a permanent pacemaker by the latest age of two months old. Conclusion: A better understanding of the aetiology of the development of CHB and identifying the risk factors in mothers is crucial for the outcomes of CHB newborns. Early diagnosis through early screening, enhanced diagnostic tools for CHB, and timely treatment of the mother may aid clinicians in better management and improve the survival rate of infants with CHB.

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.

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.

Autoimmune-associated Congenital Heart Block: A New Insight in Fetal Life.

Objective:Congenital heart block (CHB) is a rare but life-threatening disorder. More than half of CHB cases are associated with maternal autoimmune, which are termed as autoimmune-associated CHB. This review summarized the recent research findings in understanding autoimmune-associated CHB, discussed the current diagnostic approaches and management strategies, and summarized the problems and future directions for this disorder.Data Sources:We retrieved the articles published in English from the PubMed database up to January 2017, using the keywords including “Autoimmune-associated”, “Autoimmune-mediated”, and “Congenital heart block”.Study Selection:Articles about autoimmune-associated CHB were obtained and reviewed.Results:Observational studies consistently reported that transplacental maternal antibodies might recognize fetal or neonatal antigens in various tissues and result in immunological damages, but the molecular mechanisms underlying CHB pathogenesis still need illuminated. Multiple factors were involved in the process of atrioventricular block development and progression. While several susceptibility genes had been successfully defined, how these genes and their protein interact and impact each other remains to be explored. With currently available diagnostic tools, fetal ultrasound cardiography, and fetal magnetocardiography, most of CHB could be successfully diagnosed and comprehensively evaluated prenatally. The efficacy of current approaches for preventing the progression and recurrence of CHB and other autoimmune-mediated damages was still controversial.Conclusions:This review highlighted the relationships between autoimmune injuries and CHB and strengthened the importance of perinatal management and therapy for autoimmune-associated CHB.

Congenital heart block: evidence for a pathogenic role of maternal autoantibodies

During pregnancy in autoimmune conditions, maternal autoantibodies are transported across the placenta and may affect the developing fetus. Congenital heart block (CHB) is known to associate with the presence of anti-Ro/SSA and anti-La/SSB antibodies in the mother and is characterized by a block in signal conduction at the atrioventricular (AV) node. The mortality rate of affected infants is 15% to 30%, and most live-born children require lifelong pacemaker implantation. Despite a well-recognized association with maternal anti-Ro/La antibodies, CHB develops in only 1% to 2% of anti-Ro-positive pregnancies, indicating that other factors are important for establishment of the block. The molecular mechanisms leading to complete AV block are still unclear, and the existing hypotheses fail to explain all aspects of CHB in one comprehensive model. In this review, we discuss the different specificities of maternal autoantibodies that have been implicated in CHB as well as the molecular mechanisms that have been suggested to operate, focusing on the evidence supporting a direct pathogenic role of maternal antibodies. Autoantibodies targeting the 52-kDa component of the Ro antigen remain the antibodies most closely associated with CHB. In vitro experiments and animal models of CHB also point to a major role for anti-Ro52 antibodies in CHB pathogenesis and suggest that these antibodies may directly affect calcium regulation in the fetal heart, leading to disturbances in signal conduction or electrogenesis or both. In addition, maternal antibody deposits are found in the heart of fetuses dying of CHB and are thought to contribute to an inflammatory reaction that eventually induces fibrosis and calcification of the AV node, leading to a complete block. Considering that CHB has a recurrence rate of 12% to 20% despite persisting maternal autoantibodies, it has long been clear that maternal autoantibodies are not sufficient for the establishment of a complete CHB, and efforts have been made to identify additional risk factors for this disorder. Therefore, recent studies looking at the influence of genetic and environmental factors will also be discussed.

Role of Calcium Channels in Congenital Heart Block

Congenital heart block (CHB) is a conduction abnormality that affects hearts of foetuses and/or newborn to mothers with autoantibodies reactive with the intracellular soluble ribonucleoproteins 48-kD La, 52-kD Ro and 60-kD Ro. CHB carries substantial mortality and morbidity, with more than 60% of affected children requiring lifelong pacemakers. Several hypotheses have been proposed to explain the pathogenesis of CHB. These can be grouped under three main hypotheses: Apoptosis, Serotoninergic and Ca channel hypothesis. Here, we discuss these hypotheses and provide recent scientific thinking that will most likely dominate the future of this field of research.

Immunological Contribution to the Pathogenesis of Congenital Heart Block

Immunological Contribution to the Pathogenesis of Congenital Heart Block

When the levee doesn't break: A novel role of β2‐glycoprotein I to protect against congenital heart block

When the levee <i>doesn't</i> break: A novel role of β₂‐glycoprotein I to protect against congenital heart block

Anti-La (SS-B) but not anti-Ro52 (SS-A) antibodies cross-react with laminin--a role in the pathogenesis of congenital heart block?

Cross-reactions between maternally derived autoantibodies and fetal cardiac antigens have been postulated to play a role in the pathogenesis of congenital heart block (CHB). We have explored the cross-reactivity of autoantibodies to the small ribonuclear autoantigens, La/SS-B and Ro/SS-A, with laminin, the major component of cardiac sarcolemmal membrane using affinity-purified antibodies from patients with Sjögren's syndrome (SS). Anti-La antibodies purified from eight of 10 patients cross-reacted significantly with mouse laminin by ELISA. In contrast, purified antibodies to Ro52 from the same 10 patients showed little or no binding to laminin. Laminin inhibited up to 70% binding of anti-La antibodies to La antigen, and La inhibited up to 65% binding of anti-La antibodies to laminin. The cross-reaction was further examined on cryosections of 10 human fetal hearts aged from 8.7 to 14.9 weeks of gestation, two normal adult hearts, and one pathological adult heart with a diagnosis of dilated cardiomyopathy. Anti-Ro52 antibodies did not bind to the surface of cardiac cells. However, anti-La antibodies from seven of 10 patients tested bound to the surface of fetal myocytes from hearts aged 9.4 to 14.9 weeks of gestation, and also to the myocytes from the pathological adult heart but not to normal adult hearts. Preincubation with La antigen abolished the binding of anti-La antibodies to the surface of adult heart myocytes with dilated cardiomyopathy, and pre-incubation with mouse laminin could partially block this binding. These results suggest that molecular mimicry between laminin and La, but not Ro52, may act as a target for specific maternal autoantibodies, and contribute to the pathogenesis of CHB at a critical stage during fetal cardiac development.

5th International Conference on Sex Hormones, Pregnancy and Rheumatic Disease

This conference focused on pregnancy in rheumatic diseases. In antiphospholipid syndrome (APS), thrombotic phenomena, complement system and direct binding of antiphospholipid (aPL) antibodies to the trophoblast can explain the wide obstetrical manifestations. A significant rate of prematurity and intrauterine growth restriction is observed in APS pregnancies. Concerning infant health, shortand longterm outcome for babies born to patients with APS was reported; the pathogenesis of congenital heart block and its management in the first years of a child’s life was extensively discussed. Moreover, a specific session analyzed the outcome of systemic lupus erythematosus (SLE), demonstrating frequent clinical relapse during pregnancy. By contrast, rheumatoid arthritis (RA) usually improves, mainly owing to a dramatic change in the cytokines’ profile. Finally, based on experts’ opinions, recommendations for treatment with new antirheumatic drugs in pregnancy were proposed. The conference, held in Florence April 20–21, 2007, attracted over 500 attendees from 53 different countries. It was co-chaired by Maurizio Cutolo, Marco Matucci Cerinic, Angela Tincani and Pierluigi Meroni. The major topics aimed to analyze the pathogenesis of fetal damage and pregnancy complications in APS, immune modulation of RA during pregnancy, pregnancy outcome in different autoimmune diseases (i.e., SLE and systemic sclerosis [SSc]), the health status of children born to mothers with aPL antibodies or anti-Ro/SSA antibodies and, finally, some recommendations regarding drug treatment during pregnancy in patients affected by rheumatic diseases.

Impaired clearance of apoptotic cardiocytes is linked to anti-SSA/Ro and -SSB/La antibodies in the pathogenesis of congenital heart block

The role of cardiocytes in physiologic removal of apoptotic cells and the subsequent effect of surface binding by anti-SSA/Ro and -SSB/La antibodies was addressed. Initial experiments evaluated induction of apoptosis by extrinsic and intrinsic pathways. Nuclear injury and the translocation of SSA/Ro and SSB/La antigens to the fetal cardiocyte plasma membrane were common downstream events of Fas and TNF receptor ligation, requiring caspase activation. As assessed by phase-contrast and confirmed by confocal microscopy, coculturing of healthy cardiocytes with cardiocytes rendered apoptotic via extrinsic pathways revealed a clearance mechanism that to our knowledge has not previously been described. Cultured fetal cardiocytes expressed phosphatidylserine receptors (PSRs), as did cardiac tissue from a fetus with congenital heart block (CHB) and an age-matched control. Phagocytic uptake was blocked by anti-PSR antibodies and was significantly inhibited following preincubation of apoptotic cardiocytes with chicken and murine anti-SSA/Ro and -SSB/La antibodies, with IgG from an anti-SSA/Ro- and -SSB/La-positive mother of a CHB child, but not with anti-HLA class I antibody. In a murine model, anti-Ro60 bound and inhibited uptake of apoptotic cardiocytes from wild-type but not Ro60-knockout mice. Our results suggest that resident cardiocytes participate in physiologic clearance of apoptotic cardiocytes but that clearance is inhibited by opsonization via maternal autoantibodies, resulting in accumulation of apoptotic cells, promoting inflammation and subsequent scarring.

Autoimmune‐associated Congenital Heart Block: Treatment of the Mother With Immunoadsorption

Autoimmune-associated congenital heart block (CHB) is a rare complication of pregnancy in mothers with Anti-Ro/SSA antibodies (SSA-abs), resulting in fetal myocarditis, atrioventricular block, hydrops fetalis and/or intrauterine fetal death. As these antibodies are supposed to be directly involved in the pathogenesis of CHB, their removal should be associated with an improved clinical course. Extracorporeal immunoadsorption (IA) is the most efficient method to remove IgG-immunoglobulins like SSA-abs selectively. Two women with high titers of those auto-antibodies [mothers serum 615 and 612, respectively (normal range <3.0 IU/mL)] were treated with IA two to three times per gestation week in the outpatient department of the University of Rostock. In both patients, the mean removal of IgG (65 +/- 6%) to a target near 2.0 g/L after IA was successful. The SSA-abs were reduced from mean 328 +/- 138 and 247 +/- 105 pre IA to 88 +/- 124 and 98 +/- 42 post IA, respectively. One child received a pacemaker due to the persisting atrioventricular block grade III after birth. The second was unaffected. The removal of highly elevated SSA-antibodies by immunoadsorption is a possible treatment option in pregnant woman with high titers of those antibodies and/or a positive history of clinical complications. Further clinical studies are necessary.

Effect of Maternal Autoantibodies on Fetal Cardiac Conduction: An Experimental Murine Model

The pathogenesis of congenital heart block (CHB) remains unclear. The occurrence rate of neonatal CHB is low, even in murine models of lupus erythematosus. The assessment of heart block in murine maternal lupus models by measuring atrioventricular conduction in neonatal offspring is potentially confounded by fetal wastage. We therefore sought to develop a murine CHB model with a superior immune response and to use embryonic Doppler echocardiography to observe conduction system damage in the fetus. Mature 8-wk-old female C3H/HeJ mice (n=43) were immunized with 60 kD Ro, 48 kD La, or recombinant calreticulin autoantigens. ELISA confirmed that significant serum autoantibodies developed in all three immunized groups when compared with controls. Starting at 13 d of gestation, a significantly lower fetal heart rate (HR) and a higher percentage of fetal bradycardia/atrioventricular block (AVB, nonadvanced second degree) were observed in all immunized groups, compared with controls. There was 9-18% nonadvanced second-degree AVB in immunized groups and 0% in controls at <18 d of gestation. Neonatal electrocardiograms demonstrated only 1 degrees AVB in immunized groups. Maternal immunization with 60 kD Ro, 48 kD La, or recombinant calreticulin autoantigens resulted in AVB in a significant percentage of fetuses, however, lesser degrees of AVB were seen at birth. Significant fetal bradycardia and AVB may be missed by assessment only at birth in murine models of CHB due to fetal wastage.

Autoimmune-associated congenital heart block: dissecting the cascade from immunologic insult to relentless fibrosis.

Few diseases exemplify the integration of research from bench to bedside as well as neonatal lupus, often described as a model of passively acquired autoimmunity. The signature histologic lesion of autoimmune congenital heart block (CHB) is fibrosis of the conducting tissue and, in some cases, the surrounding myocardium. Although anti-SSA/Ro-SSB/La antibodies are detected in > 85% of mothers whose fetuses are identified with conduction abnormalities in a structurally normal heart, the risk for a woman with the candidate antibodies to have a child with CHB is 2%. The mechanism by which maternal anti-SSA/Ro-SSB/La antibodies initiate and finally eventuate in atrioventricular nodal scarring is not yet defined, but it is clear that the antibodies alone are insufficient to cause disease and fetal factors are likely contributory. Previous in vitro and in vivo studies suggest that the pathologic cascade is initiated via apoptosis, resulting in translocation of SSA/Ro-SSB/La antigens to the cell surface where they are bound by maternal autoantibodies. Subsequently, the Fc portion of the bound immunoglobulin engages Fcgamma receptors on tissue macrophages, resulting in release of TGF-beta at a threshold favoring a profibrotic milieu and irreversible scarring. This cascade also involves tissue-specific activation of TGF-beta, which promotes the modulation of fibroblasts into myofibroblasts, a scarring phenotype. Recent findings point to genetic polymorphisms that promote high production of TGF-beta as possible fetal risk factors for CHB. Further elucidation of maternal and fetal contributory factors should provide insight into the pathogenesis of CHB and the rarity of irreversible injury.

Down-regulation of L-type calcium channel in pups born to 52 kDa SSA/Ro immunized rabbits.

Congenital heart block is considered a model of passively acquired autoimmune disease in which the mother generates anti-SSA/Ro and/or anti-SSB/La antibodies that cross the placenta and presumably injure the heart of developing fetus. CHB is accompanied by ECG abnormalities including AV block, sinus bradycardia, and ventricular dysfunction. Our previous data indicate that these abnormalities are caused by maternal autoantibody-mediated disturbance of L-type Ca channels. To investigate the consequence of chronic exposure of L-type Ca channels in newborn pups to maternal autoantibodies during pregnancy, we immunized female rabbits with human 52 kDa-SSA/Ro (Ro52) recombinant protein. ECG revealed that pups from the immunized group had varying degrees of conduction defects. In addition, I(CaL) density and protein were reduced in hearts of pups from the immunized group. Sera and purified IgG from immunized rabbits inhibited I(Ba) recorded from oocytes with expressed alpha(1C) and beta(2a) subunits of L-type Ca channel. Pups born to Ro52 immunized mothers exhibited down-regulation of L-type calcium channels in heart. The data provide new insight into the pathogenesis of congenital heart block.

Electrocardiographic abnormalities in a murine model injected with IgG from mothers of children with congenital heart block.

It is a widely held view that congenital heart block (CHB) is caused by the transplacental transfer of maternal autoantibodies (anti-SSA/Ro and/or anti-SSB/La) into the fetal circulation. To test this hypothesis and to reproduce human CHB, an experimental mouse model (BALB/c) was developed by passive transfer of human autoantibodies into pregnant mice. Timed pregnant mice (n=54) were injected with a single intravenous bolus of purified IgG containing human anti-SSA/Ro and anti-SSB/La antibodies from mothers of children with CHB. To parallel the "window period" of susceptibility to CHB in humans, 3 groups of mice were used: 8, 11, and 16 days of gestation. Within each group, we tested 10, 25, 50, and 100 microg of IgG. At delivery, ECGs were recorded and analyzed for conduction abnormalities. Bradycardia and PR interval were significantly increased in 8-, 11-, and 16-day gestational groups when compared with controls (P<0.05). QRS duration was not significantly different between all groups. Antibody levels measured by ELISA in both mothers and their offspring confirmed the transplacental transfer of the human antibodies to the pups. The passive transfer model demonstrated bradycardia, first-degree but not complete atrioventricular block in pups. The greater percentage and degree of bradycardia and PR prolongation in the 11-day mouse group correlates with the "window period" of susceptibility observed in humans. The high incidence of bradycardia suggests possible sinoatrial node involvement. All together, these data provide relevant insights into the pathogenesis of CHB.

Serum and immunoglobulin G from the mother of a child with congenital heart block induce conduction abnormalities and inhibit L-type calcium channels in a rat heart model.

Although a strong clinical association exists between congenital heart block (CHB) and an immune response to SSA/Ro and SSB/La proteins, a causative role of these antibodies in the pathogenesis is just emerging. In a preliminary report, we have demonstrated that IgG fractions isolated from the sera of mothers whose children have CHB are arrhythmogenic in the human fetal heart. To more precisely define the arrhythmogenic effect of anti-SSA/Ro-SSB/La antibodies, we used the readily available rat heart model to record: 1) ECGs from Langendorff beating hearts; 2) action potentials from atrioventricular (AV) nodal preparations; 3) L-type Ca currents, I(Ca) at the whole-cell and single channel levels; and 4) other currents such as the transient outward K+ current, I(to), the inward rectifier K+ current, I(K1), and the Na+ current, I(Na). Perfusion of hearts with purified IgG (800 microg/mL), isolated from the serum of a mother with SSA/Ro and SSB/La antibodies whose child had CHB, resulted in bradycardia associated with 2:1 AV block. Simultaneous action potentials were recorded from dissected atrial and AV nodal areas of the rat heart. Superfusion of these preparations with the same mother's IgG fraction resulted in 2:1 AV block followed by complete inhibition of AV nodal action potential. Because AV nodal electrogenesis is largely dependent on I(Ca), the effect of these antibodies on I(Ca) was subsequently determined. Superfusion of myocytes with whole serum or purified IgG (80 microg/mL) from the same mother consistently inhibited whole cell I(Ca), ensemble average Ba2+ currents (I(Ba)) and open state probability, p(o), without affecting the channel conductance. IgG had no significant effect on I(to), I(K1), or I(Na). Whole sera and IgG fractions from a healthy mother with no detectable anti-SSA/Ro or SSB/La antibodies did not inhibit I(Ca) or I(Ba). These results demonstrate that IgG containing anti-SSA/Ro and -SSB/La antibodies induces complete AV block in beating hearts and in multicellular preparations, thus implicating a preferential interaction of these autoantibodies with Ca channels and/or associated regulatory proteins. This is consistent with the observed inhibition of Ca channels that may be a critical factor contributing to the pathogenesis of CHB.

Immunological aspects of congenital atrioventricular block.

Isolated congenital heart block (CHB) in children is strongly associated with the occurrence of autoantibodies to Ro/SS-A and La/SS-B in the circulation of the mother. Although these antibodies are generally found in patients with generalized autoimmune diseases, they may also occur in symptomless mothers of CHB patients. It is thought that anti-Ro/SS-A and anti-La/SS-B may reach the fetal circulation via transplacental transport, starting around the 20th week of gestation. Although several hypotheses have been put forward, the exact mechanism through which these autoantibodies bind the fetal conduction system and elicit a local inflammatory response is still unclear. Also, the induction of the autoantibody response in the mother remains largely obscure, although a putative role of viral infection has been suggested. In this overview, the structure of the involved antigens will be discussed, followed by the nature of the antibodies. Recent data regarding the etiology of the anti-Ro/SS-A and anti-La/SS-B response and the role of these autoantibodies in the pathogenesis of CHB will be presented.

Pregnancy in systemic lupus erythematosus: Contraception, fetal outcome and congenital heart block

Acta Obstetricia et Gynecologica ScandinavicaVolume 73, Issue 6 p. 517-518 Pregnancy in systemic lupus erythematosus: Contraception, fetal outcome and congenital heart block Heikki Julkunen, Corresponding Author Heikki Julkunen 1Fourth Department of Medicine and the First and Second Departments of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki, FinlandFourth Department of Medicine Helsinki University Central Hospital Unioninkatu 38 SF-00170, Helsinki, FinlandSearch for more papers by this author Heikki Julkunen, Corresponding Author Heikki Julkunen 1Fourth Department of Medicine and the First and Second Departments of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki, FinlandFourth Department of Medicine Helsinki University Central Hospital Unioninkatu 38 SF-00170, Helsinki, FinlandSearch for more papers by this author First published: July 1994 https://doi.org/10.3109/00016349409013445Citations: 7AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article.Citing Literature Volume73, Issue6July 1994Pages 517-518 RelatedInformation

Anti-SS-A/Ro SS-B/La antibodies bind to neonatal rabbit cardiac cells and preferentially inhibit in vitro cardiac repolarization

The neonatal lupus syndrome is the most common cause of isolated congenital heart block. There is, at present, little information about the putative role of anti-SS-A/Ro SS-B/La antibodies in the pathogenesis of congenital heart block in the neonatal lupus syndrome. Using an in vitro experimental model, the present study was designed to test the hypothesis that IgG antibodies in the sera of anti-SS-A/Ro SS-B/La-positive> mothers of infants with isolated congenital heart block bind to and affect the transmembrane action potential of rabbit cardiac tissue. The results demonstrate a preferential inhibition of membrane repolarization (ADP-50 and ADP-90) and staining of cardiac cells within the neonatal, in contrast to the adult, rabbit heart by sera and IgG-enriched fractions from anti-SS-A/Ro SS-B/La-positive individuals. The results of the electrophysiologic studies demonstrate a pathophysiologic role for the IgG fraction of anti-SS-A/Ro SS-B/La-positive maternal sera in inhibiting neonatal rabbit cardiac repolarization. It is possible that antibodies to similar determinants expressed on the cell membrane of cardiac-conducting cells also may play a pathophysiologic role in the development of idiopathic congenital heart block in humans.