Complete congenital heart block is associated with increased autoantibody titers against calreticulin

Complete congenital heart block (CCHB) is associated with anti-Ro/SS-A and anti-La/SS-B antibodies. Calreticulin, a calcium-binding, multifunctional protein of the endoplasmic reticulum with C-terminal KDEL-sequence, is not part of the Ro/SS-A ribonucleoprotein complex. In this study anti-calreticulin autoantibody responses in serum samples from 18 infants with CCHB, their mothers and in a control group of 11 anti-Ro/SS-A or anti-La/SS-B positive infants without heart block and their mothers were analysed. Specific enzyme-linked immunosorbent assays were performed. Nine out of 18 sera with CCHB contained IgG anti-calreticulin antibodies. Four sera of those with IgG antibodies also had IgM antibodies. One serum contained anti-calreticulin IgM antibodies only. In the non-CCHB group two sera were positive for IgG and one serum was positive for IgM anti-calreticulin antibodies. Sera of healthy infants were negative both for anti-IgG and anti-IgM calreticulin antibodies. Calreticulin is involved in calcium storage and therefore anti-calreticulin antibodies might influence the development of CCHB. The new finding of IgM autoantibodies and the observed differences in antibody response in infants and mothers support the hypothesis of a fetally mediated and passively acquired autoimmune disease.     

Fetal Doppler echocardiographic diagnosis and successful steroid therapy of Luciani-Wenckebach phenomenon and endocardial fibroelastosis related to maternal anti-Ro and anti-La antibodies.

BACKGROUND: Complete fetal heart block (HB) and endocardial fibroelastosis (EFE) are known to be associated with maternal anti-Ro and anti-La antibodies. Complete fetal HB is irreversible. OBJECTIVES: We sought to (1) assess the value of the superior vena cava/ascending aorta Doppler approach in the early detection of abnormal delay in the fetal atrioventricular (AV) time of conduction, before appearance of complete fetal HB; and (2) report the effect of prenatal steroid therapy on EFE, HB, or both. RESULTS: The clinical history, echocardiographic, and Doppler investigations of 3 fetuses and children born to mothers positive for anti-Ro and anti-La antibodies are reported. Two fetuses presented with EFE either isolated (29 weeks) or associated with AV block (25 weeks). In this last case, the superior vena cava/ascending aorta approach allowed the identification of a Luciani-Wenckebach phenomenon. In a third fetus, 2:1 AV block was noted at 23 weeks of gestation. Dexamethasone (4 mg/day) was administered to all 3 patients. Complete regression of the EFE and conduction abnormalities was documented in all cases. CONCLUSION: Early prenatal detection of abnormal delay in fetal AV time conduction is possible with the Doppler superior vena cava/ascending aorta approach. Steroid therapy can cure fetal EFE and AV conduction delays associated with maternal anti-Ro and anti-La antibodies.     

Diagnosis and Management of Fetal Bradyarrhythmias

Complete atrioventricular block (CAVB) is the most common cause of persistent fetal bradycardia. In the presence of a structurally normal heart, it develops primarily in anti-Ro and anti-La positive antibody pregnancies after 20 weeks of gestation. There is a significant risk of perinatal demise, particularly in association with fetal hydrops, poor ventricular function, and heart rates < 55 beats/min. Transplacental treatment strategies are aimed at preventing or modulating these risk factors. Maternal administration of dexamethasone to mitigate or prevent concomitant myocardial inflammation, in combination with β-stimulation for persistent fetal bradycardia < 55 beats/min to increase fetal cardiac output, has resulted in significantly improved fetal and neonatal outcomes without reversing CAVB.     

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 autoantihodies 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 tbis 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 autoantihodies in the pathogenesis of CHB will he presented.     

Successful outcome in a fetus with an extremely low heart rate due to isolated complete congenital heart block.

Isolated complete congenital heart block (CCHB) in a fetus is usually associated with the presence of autoantibodies to SSA (Ro) and SSB (La) antigens in the maternal circulation. Although the prognosis for the majority of fetuses is good, it is less favorable in fetuses with a ventricular rate < 55 bpm in early pregnancy or with a decrease in the ventricular rate by >/= 5 bpm during pregnancy. It is not known if the same prognostic criteria apply for the occasional fetus with isolated non-autoimmune CCHB. We report a case of a single fetus with an isolated non-autoimmune CCHB with an extremely low ventricular rate (37 bpm) in which the outcome was favorable. Dilated cardiomyopathy is a rare complication in patients with isolated CCHB, despite early institution of cardiac pacing, and is usually recognized after several months of relative well-being. It is assumed that in the majority of patients it represents a sequel to in utero autoimmune or postnatal reactivation myocarditis. However, the possibility of a tachycardia-induced cardiomyopathy caused by an excessively high pacing rate should also be taken into consideration, as was clearly demonstrated in our patient.     

Cellular mechanism of the conduction abnormalities induced by serum from anti-Ro/SSA-positive patients in rabbit hearts.

In this study, IgG fractions from sera of SLE patients with anti-Ro/SSA or anti-Ro/SSA and anti-La/SSB activity were tested in Langendorff preparations of adult rabbit hearts, aiming to reproduce the cardiac manifestations observed in neonatal lupus in an experimental model. The hearts were perfused with normal Tyrode's solution for 30 min, followed by perfusion with Tyrode's containing 0.3 mg/ml of anti-Ro/SSA- (or anti-Ro/La-) positive IgG (nine sera), anti-ribonucleoprotein (RNP)-positive IgG (five sera), or IgG fractions from normal donors (five sera). In one third of the experiments done with anti-Ro/La-positive IgG, heart block was observed. With the remaining fractions, a decrease in heart rate of 17.1% was observed, but normal sinus rhythm was maintained. The IgG fractions with anti-RNP activity (five experiments) and from normal sera (six experiments) reduced heart rates by 12.9 and 3.3%, respectively, but heart block was not observed. To further characterize the cellular mechanisms involved in the conduction disturbances observed in the whole rabbit hearts, we conducted experiments with ventricular myocytes isolated from young rabbit hearts, studied by whole cell patch-clamp technique. In these experiments, the slow inward currents were analyzed during the superfusion of the cell with normal Tyrode's solution and 5 min after superfusion with Tyrode's solution containing 0.3 mg/ml of anti-Ro/SSA- (or anti-Ro/La-) positive IgG (five sera), anti-RNP-positive IgG (three sera), or IgG from normal donors (four sera). Resting and action potential amplitudes were not affected by any of the sera used. The anti-Ro/SSA IgG fraction induced a mean reduction in the peak slow inward current of 31.6%. IgG fractions with anti-RNP activity reduced slow inward current by 4.4%, whereas IgG fractions from normal donors increased this current by 3.3%. IgG-free fractions from sera of patients with anti-Ro/SSA activity did not alter the peak slow inward current. These results show, for the first time, that the presence of anti-Ro/SSA or anti-Ro/SSA and anti-La/SSB antibody activity in IgG fractions from lupus patients' sera can induce cardiac conduction disorders similar to those observed in neonatal lupus.     

Single Pass VDD Pacing in Children and Adolescents

Use of a single pass lead for VDD pacing in complete heart block is well described in adults, but there are only brief reports of its use in children. We have used standard adult size single pass leads in 13 children and adolescents aged 3.7–17.2 years (mean 10.1 years) and weighing 13.5–76 kg (mean 34.8 kg). Congenital complete heart block was present in 7 patients, surgical complete heart block in 5 patients and 2:1 AV block of unknown cause in 1 patient. In four patients, the VDD system was their first pacing system. In nine of the patients, 1–6 previous systems had been used and simultaneous extraction of ventricular leads and/or atrial leads was performed. Leads of four different types were used: Brilliant IMPl5Q, Brilliant + IMR15Q, CapSure 5032, and Unipass 425–13 with 4 different generators: Saphir 600, SaphirII620, Thera VDD 8948, and Unity 292–07. At implantation, via a subclavian vein puncture, excess lead was advanced into the right atrium to allow both atrial sensing and slack for further growth. Ventricular thresholds ranged from 0.2–0.7 V. The minimal atrial amplitude was 0.7–4 mV and the maximum amplitude was 2.5–8 mV. There were no complications. Ail patients have maintained adequate atrial signals for reliable pacing with follow up of 3–36 months (mean 17.6 months) during which time some have undergone considerable growth. Beliable atrial synchronous ventricular pacing is possible in growing children with complete heart block using a standard adult single pass lead.     

Echocardiographic features and outcome of restrictive foramen ovale in fetuses with and without cardiac malformations: Literature review

Foramen ovale is a small communication between the left and the right atrium and its restriction is a rare congenital heart anomaly. There is no consensus on diagnosis and management of fetal restrictive foramen ovale (RFO). In our paper we included 11 studies about fetuses affected by isolated RFO, RFO with D-Transposition of the Great Arteries (dTGA) and RFO with hypoplastic left heart syndrome (HLHS). While fetuses affected from HLHS and dTGA with RFO have a poor prognosis, premature RFO in an otherwise structurally normal heart, if found in later gestation, have an overall good outcome.     

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.     

A shared idiotype among human anti-Ro/SSA autoantibodies [published erratum appears in J Exp Med 1990 Feb 1;171(2):591]

Idiotypes and antiidiotypes are thought to be important immune regulators and have provided clues for the origin and pathogenicity of autoantibodies. Many lupus and Sj?gren's syndrome patients, as well as most neonatal lupus infants with congenital heart block or dermatitis, have antibodies to the ribonucleoprotein Ro/SSA, which is one of a group of RNA-protein autoantigens commonly found in human lupus sera. To characterize the fine specificity of anti-Ro/SSA antibodies, a rabbit antidiotypic serum was prepared against polyclonal affinity purified anti-Ro/SSA F(ab')2. The resulting antiidiotype, anti-Id-Rol, is specific for the F(ab')2 fraction of the anti-Ro/SSA immunogen and its binding to anti-Ro/SSA is inhibited by purified Ro/SSA. These data indicate that the Id-Rol epitope on anti-Ro/SSA is associated with the antigen binding site of these same antibodies. The Id-Rol idiotype was present by ELISA in 3 of 12 additional anti-Ro/SSA preparations from precipitin-positive donor sera and in anti-Ro/SSA from one normal donor with low level antibody. This is the first shared idiotype to be found in the human autoantibodies binding to this RNA-protein antigen. Idiotypic differences between anti-Ro/SSA autoantibodies have the potential to explain the variation in pathologic associations found in individuals who develop this autoantibody specificity.     

Obstetric aspects of the Prader-Willi syndrome.

The Prader-Willi syndrome (PWS) is a complex, multisystem disorder. The syndrome affects the central nervous system, with a predilection for the hypothalamus. The clinical picture in PWS is very variable, and depends on the age of the affected child. Frequently, the most prominent features such as obesity, mental retardation and behavioral disorders do not become evident until the later childhood stage, which can lead to underdiagnosis or late diagnosis in early childhood. Because of the long-term implications of this syndrome, it is important to recognize its features as soon as possible so that early counseling of parents and the affected child is possible. Because PWS can also lead to complications in both pregnancy and labor, proper diagnosis in the fetus can also help optimize perinatal care in affected children. In three cases we illustrate that certain combinations of obstetric symptoms such as polyhydramnios, diminished fetal movements, malpresentation and abnormal fetal heart rhythm can help alert clinicians to the possibility of this syndrome in fetuses.     

Fetal echocardiography: a large clinical experience and follow-up

We reviewed our experience with 382 fetal echocardiograms. Complete studies were not possible for three pregnancies because of either fetal position or maternal obesity. Studies were performed for fetal arrhythmia (28%), maternal factors (21%), fetal anomaly (11%) and family history of congenital heart disease (40%). There was a recurrence of heart disease in two of 153 patients (1.3%). Arrhythmia was the most common finding (82 of 382 patients). Premature atrial and ventricular contractions were the most common arrhythmia, and structural defects were present in four of 58 patients (6.8%) with premature contractions. Fetal heart defects (n = 44) were identified in 40 of 382 (10%) referrals. The defects were complete atrioventricular block (13), ventricular septal defect (4), atrioventricular canal (5), cardiac mass (3), ectopia cordis (2), thoracopagus (2), hypoplastic left ventricle (2), hypoplastic right ventricle (2), atrial flutter (2), pulmonic stenosis (1), single ventricle (2), Uhl's anomaly (1), Ebstein's anomaly (1), mitral atresia (1), d-transposition of the great vessels (1), tetralogy of Fallot with absent pulmonary valve (1), and atrial septal defect and ventricular septal defect (1). There were three false positive (99% specificity) and two false negative (95% sensitivity) fetal echocardiograms. The survival rates for referred patients with heart defects was: live born and perinatal survivor, 54%; perinatal death, 31%; still birth, 11%; and termination of pregnancy, 4%. Fetal echocardiography is accurate, and the abnormalities detected appear to be more severe than those detected on newborn screening.     

Ro/SSA autoantibodies directly bind cardiomyocytes, disturb calcium homeostasis, and mediate congenital heart block

Congenital heart block develops in fetuses after placental transfer of Ro/SSA autoantibodies from rheumatic mothers. The condition is often fatal and the majority of live-born children require a pacemaker at an early age. The specific antibody that induces the heart block and the mechanism by which it mediates the pathogenic effect have not been elucidated. In this study, we define the cellular mechanism leading to the disease and show that maternal autoantibodies directed to a specific epitope within the leucine zipper amino acid sequence 200-239 (p200) of the Ro52 protein correlate with prolongation of fetal atrioventricular (AV) time and heart block. This finding was further confirmed experimentally in that pups born to rats immunized with p200 peptide developed AV block. p200-specific autoantibodies cloned from patients bound cultured cardiomyocytes and severely affected Ca2+ oscillations, leading to accumulating levels and overload of intracellular Ca2+ levels with subsequent loss of contractility and ultimately apoptosis. These findings suggest that passive transfer of maternal p200 autoantibodies causes congenital heart block by dysregulating Ca2+ homeostasis and inducing death in affected cells.     

Clinical, Electrophysiological Characteristics, and Radiofrequency Catheter Ablation of Atrial Tachycardia Near the Apex of Koch's Triangle

Atrial tachycardia, with its focus near the apex of Koch's triangle, may carry a potential risk of atrioventricular block during radiofrequency catheter ablation. The efficacy and safety of this procedure have never been addressed. The characteristics and catheter ablation results are reported for six patients with atrial tachycardia near the apex of Koch's triangle. All six patients were female aged 49.6 ± 9.3 years (range 39–63). Organic heart disease was present in 3 (50%) of the 6 patients. The P wave in surface ECG had a mean axis of − 28° (range − 90°–+ 30°) in the frontal plane. The catheter ablation was guided by activation sequence mapping. The energy was titrated from low power level. Atrial overdrive pacing was used to monitor the atrioventricular conduction should accelerated functional rhythm occur. At the final successful ablation site, the local atrial activation was 41.8 ± 9.1 ms before the P wave and His-bundle potential was present in 5 of the 6 patients. All patients had their atrial tachycardia eliminated without recurrence or heart block during a follow-up period of 17.7 ± 8.5 months (range 6–30). In conclusion, atrial tachycardia near the apex of Koch's triangle has distinct clinical and electrophysiological features, Radiofrequency catheter ablation can be performed effectively. However, extreme care must be taken to prevent inadvertent atrioventricular block. Titrated energy application and continuous monitoring of atrioventricular conduction are mandatory.     

Neonatal lupus erythematosus with congenital heart block and severe heart failure due to myocarditis and endocardititis of the mitral valve

We report a case of neonatal lupus erythematosus (NLE) with congenital heart block and severe myocardial failure, which was followed from the 25th week of gestation because of fetal bradycardia. The child was delivered at the 37th week of gestation by elective cesarean section because of echocardiographically documented heart enlargement, pericardial effusion and moderate insufficiency of the mitral and tricuspid valves. In spite of immediate pacing, intubation and supportive treatment, the newborn developed progressive heart failure. Echocardiography showed endocarditis of the mitral valve and diffuse myocarditis. The heart failure resolved under steroid treatment. Our experience supports the early use of steroids in treating myocarditis due to NLE. Intrauterine steroid treatment in the presence of fetal hydrops and congenital heart block is discussed.     

Fetal Heart Block: A New Experimental Model to Assess Fetal Pacing

Epicardial fetal pacing via thoracotomy has the potential of being a safer and more reliable procedure to treat congenital complete heart block (CHB) associated with fetal hydrops refractory to medical therapy. To assess the acute electrophysiological characteristics of two ventricular epicardial leads, a new experimental model of fetal heart block induced by cryosurgical ablation of the AV node without the need for fetal cardiac bypass was performed in 12 pregnant ewes at 110–115 days gestation. A modified screw-in lead (1½ turns) was used in six fetal lambs and a stitch-on lead in the other six lambs. CHB was achieved in 100% of the fetal lambs, with no ventricular escape rate noticed in any of the lambs. The acute stimulation thresholds were consistently low for both leads, with lower values for the screw-in lead at pulse duration below 0.9 msec (P < 0.03). Current measured at voltage threshold with pulse width below 0.5 msec was lower for the screw-in lead (P < 0.048). Stimulation resistance, measured during constant-voltage pacing, was not statistically different between the two leads (441.8 ± 13.7 Ω for the screw-in lead vs 480.2 ± 59.2 Ω for the stitch-on lead). No significant differences (P > 0.20) were found in R wave amplitude between the two electrodes. Slew rates were significantly higher in the screw-in group than in the stitch-on group (1.40 ± 0.2 vs 0.62 ± 0.2 V/sec, P = 0.04). This model of CHB is a simple and reproducible method to assess fetal pacing. We find the screw-in electrode to be a better option when fetal pacing is indicated.     

The Monolithic Fetal Pacemaker:

DELL'ORFANO, J., et al .: The Monolithic Fetal Pacemaker: Prototype Lead Design for Closed Thorax Deployment. Prenatal sudden cardiac death and hydrops fetalis are often due to complete heart block. However, no pacing modality exists for intrauterine application for fetal bradycardia. A prototype lead for a novel fetal pacemaker has been developed and used in a direct pacing model. It has been demonstrated that the lead can be safely and successfully deployed using a hypochondriac and transdiaphragmatic or subxiphoid approach. Pacing with ventricular capture was evident with the widening of QRS duration from   50.2 ± 9.8   to   95.1 ± 12.8 ms (P = 0.0001)   . Further studies by echocardiogram revealed an increase in the pulse with pacing, confirming pacing. This study documents proof-of-concept for closed thorax over-the-wire deployment of a novel lead design applicable to fetal pacing. By combining the lead design with microcircuitry and a small power source, it is possible to create a monolithic fetal pacemaker system capable of being deployed in utero. (PACE 2003; 26[Pt. I]:805–811)     

Alteration of the Fetal Heart Rate Pattern Induced by the Use Of Clozapine during Pregnancy

Patients treated with clozapine show autonomic dysregulation and cardiac repolarisation changes. As clozapine crosses the placenta, it could have an impact on the fetus heart rate. We reported a case of reduction of the fetal heart rate variability in a patient treated with clozapine during her pregnancy. This anomaly disappeared with fetal maturation and it did not jeopardize the fetal well-being. This side effect had already been described and pharmacologists and obstetricians should be aware that clozapine may be responsible for these fetal heart rate alterations.     

High-risk pregnancy. Identification and monitoring to improve outcome

High-risk pregnancy is a problem that directly affects both the patient and the physician. Technological advances have provided improved methods of monitoring the fetus, especially through ultrasonography and electronic fetal heart rate monitoring. However, it is still up to the physician to identify the pregnancy at risk and to properly interpret the information obtained by monitoring. To date, expert clinical management still offers the best hope for a good obstetric outcome.     

母体抗SSA/SSB抗体阳性胎儿完全性房室传导阻滞超声表现

目的 观察母体抗SSA/SSB抗体阳性胎儿完全性房室传导阻滞（CAVB）超声表现。方法 以二维、M型及多普勒超声技术观察7胎母体抗SSA/SSB抗体阳性CAVB胎儿心脏,获取二尖瓣、左心室流入道及流出道、脐动脉（UA）、静脉导管（DV）及大脑中动脉（MCA）血流频谱。结果 7名孕妇抗SSA抗体、抗Ro52抗体均呈阳性,其中4名抗SSB抗体呈阳性。7胎均见房室分离,心房律正常而心室律缓慢,二尖瓣、UA、DV及MCA血流异常;其中4胎心房壁、房间隔、二尖瓣环或腱索回声增强。7胎均未合并其他心内外结构畸形。结论 母体抗SSA/SSB抗体阳性可致胎儿发生CAVB;超声观察胎儿心脏及血流动力学变化有利于判断胎儿预后。