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The late development of heart block in paediatric patients following device closure of a perimembranous ventricular septal defect may be a cause for concern.
The development of hydrops fetalis in cases of isolated complete heart block is associated with a very poor prognosis. Various pharmacological strategies have been proposed, involving both direct fetal access and transplacental therapy, with inconsistent results in small numbers of subjects. The optimal antenatal management will remain uncertain until multicentre controlled trials are organised. We report the complete resolution of fetal hydrops at 30 weeks of gestation using combination of maternal digoxin and dexamethasone therapy, despite persistence of the complete heart block. A Caesarean section was performed at 37 weeks of gestation due to evidence of fetal intrauterine growth restriction. The baby girl is now 8 months of age and remains well, with a heart rate of 45-50 beats per minute on no medication and without pacing.
Complete congenital heart block (CCHB) is associated with anti-Ro/SS-A and anti-La/SS-B antibodies. Calreticulin, a calcium-binding, multi-functional 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.
The detection of congenital complete heart block (CCHB) in a fetus should alert the obstetrician that the welfare of both the mother and the newborn infant may be in jeopardy. An awareness of this uncommon cause of fetal bradycardia and judicious intrapartum monitoring can avert hasty and unnecessary cesarean section for suspected fetal asphyxia. Neonatal consequences may range from no effect to life-threatening congestive heart failure. The apparently healthy mothers of these infants may be at increased risk for the subsequent development of collagen vascular disease. Three recent case reports demonstrate the spectrum of neonatal and maternal disease that may accompany CCHB. The significance of abnormal serology suggesting a propensity for collagen vascular disease in an otherwise healthy parturient is discussed, and a program for follow-up is proposed.
We describe a patient with Wegener's granulomatosis (WG) who developed complete heart block. Prompt treatment with steroids and cyclophosphamide led to regression of the complete heart block. The patient was left with a persistent first degree atrio-ventricular block, however. Early treatment may obviate the need for permanent pacing in such cases.
OBJECTIVE: To identify the fine specificity patterns of maternal anti-SS-A/Ro and anti-SS-B/La antibodies that are associated with the birth of a child with transient or permanent manifestations of neonatal lupus syndromes, and to suggest a predictor algorithm for use in counseling. METHODS: Sera were obtained from 4 groups of mothers: 57 whose children had congenital heart block, 12 whose children had transient dermatologic or hepatic manifestations of neonatal lupus but no detectable cardiac involvement, 152 with systemic lupus erythematosus and related autoimmune diseases, who gave birth to healthy infants, and 30 with autoimmune diseases whose pregnancy resulted in miscarriage, fetal death, or early postpartum death unrelated to neonatal lupus. Antibodies to SS-A/Ro and SS-B/La were assessed by enzyme-linked immunosorbent assay (ELISA) and by sodium dodecyl sulfate (SDS)-immunoblot. RESULTS: Anti-SS-A/Ro antibodies were identified by ELISA in 100%, 91%, 47%, and 43% of the mothers of infants with heart block, with transient neonatal lupus, healthy infants, and fetal death, respectively. High titers of anti-SS-A/Ro antibodies were present more often in mothers of children with cardiac disease or transient neonatal lupus than in either of the other 2 groups. Maternal antibodies to SS-B/La were detected by ELISA in 76% of the heart block group, 73% of the cutaneous neonatal lupus group, 15% of the group with healthy children, and 7% of the fetal death group. On SDS-immunoblot, sera from 91% of the heart block group mothers who had antibodies to SS-A/Ro but not to SS-B/La recognized at least 1 SS-A/Ro antigen, with significantly greater reactivity against the 52-kd component. In contrast, only 62% of the anti-SS-A/Ro positive, anti-SS-B/La negative responders in the healthy group recognized the 52-kd and/or the 60-kd component. Although there was no profile of anti-SS-A/Ro response unique to the mothers of children with heart block or cutaneous manifestations of neonatal lupus, only 1% of the healthy infants were born to mothers with antibodies directed to both the 52-kd SS-A/Ro and 48-kd SS-B/La antigens and not to the 60-kd SS-A/Ro antigen. CONCLUSION: Women with antibodies to both SS-A/Ro and SS-B/La have an increased risk of giving birth to children with neonatal lupus, especially if the anti-SS-A/Ro response identifies the 52-kd component on SDS-immunoblot. Women whose sera contain only anti-SS-A/Ro antibodies in low titer and only recognize determinants that are altered by conditions of SDS-immunoblot have a low risk for giving birth to a child with neonatal lupus. Specific antibody profiles do not distinguish among the manifestations of the neonatal lupus syndromes.
OBJECTIVE: To prospectively investigate the development of fetal heart block in anti-SSA/Ro 52-kd-positive women, and to evaluate the usefulness of serial Doppler echocardiography in detecting early signs of congenital heart block. METHODS: Twenty-four women with anti-SSA/Ro 52-kd antibodies and consequently increased risk for fetal heart block were followed up weekly, between 18 and 24 weeks of gestation, with two Doppler echocardiographic methods designed to estimate the time delay between hemodynamic events caused by atrial and ventricular depolarizations. Two hundred eighty-four women with normal pregnancies served as controls. Anti-Ro 52-kd, anti-Ro 60-kd, and anti-La antibodies were investigated by immunoblotting and enzyme-linked immunosorbent assay using recombinant proteins. RESULTS: In anti-Ro 52-kd-positive women, fetal atrioventricular (AV) time intervals were longer and heart rates were slightly lower compared with those in controls. Eight of 24 fetuses had signs of first-degree block. One of these fetuses had progression to complete block, and another showed recovery from second-degree block to first-degree block with betamethasone treatment. In the remaining 6 fetuses, spontaneous normalization occurred before or shortly after birth. Fetuses with normal AV time intervals at 18-24 weeks had normal electrocardiographic results at birth. CONCLUSION: Anti-Ro 52-kd-positive pregnant women frequently carry fetuses with Doppler echocardiographic signs of first-degree AV block. These blocks revert spontaneously in the majority of fetuses, but progression to a more severe degree of block may occur in some. Serial Doppler echocardiographic measurement of AV time intervals is suggested as a useful method for surveillance of these high-risk pregnancies.
The authors present the case of a 44-year-old man who was admitted with complete heart block and signs of severe bradycardia. After steroid administration and temporary pacemaker treatment the complete heart block resolved. During this therapy transient ST segment and T wave abnormalities occurred. The positive Borrelia burgdorferi antibody titer arrived only after therapy had been completed. This is regarded as the first case of Lyme carditis with complete heart block diagnosed in eastern Europe. Carditis resolved without antibiotic treatment and has not recurred.
We studied valvular regurgitation (pulmonary, aortic, tricuspid and mitral regurgitation) in 30 patients with complete heart block by color Doppler echocardiography, pulse Doppler and continuous wave Doppler echocardiography. The prevalence rate of multivalvular regurgitation of these subjects was 83.3%. Regurgitation involving all four valves appeared in 30.0% of these patients. The prevalence rate of pulmonary, aortic, tricuspid and mitral regurgitation was 56.7%, 33.3%, 100%, and 76.7% respectively. Pulmonary regurgitation (PR) was observed in patients with complete heart block without pulmonary hypertension. PR velocity was slow and interrupted by atrial contraction. It might be possible to evaluate atrial pressure from the interruption of PR. Tricuspid regurgitation (TR) during systole was often present in patients with right ventricular endocardial pacing. Systolic TR was influenced by atrial contraction. When atrial contraction occurred during systole, TR was interrupted, or shortened. Diastolic TR and MR were easily detected by M mode color Doppler echocardiography. The diastolic TR and MR were of slow velocity and appeared 240-290 msec after P wave. These atypical valvular regurgitation in patients with complete heart block reflect of the inverse atrial-ventricular pressure gradient across the atrio-ventricular valve.
Autoantibodies against amino acid 200-239 (p200) in the predicted leucine zipper region of the Ro52 protein are associated with congenital heart block, a potentially fatal condition that may affect fetuses of women with Ro52 autoantibodies. To allow detailed studies of the antibodies associated with congenital heart block, B-cell derived combinatorial antibody libraries from patients were screened for Ro52 and p200 specific antibody clones. Two human monoclonal anti-p200 antibody fragments, S3A8 and M4H1, were isolated and analysed with regard to VHand VL gene utilization, somatic mutations and binding properties. Both identified clones recognized recombinant and native intact Ro52, and reacted only with p200 in a set of related Ro52 peptides. The specificity and affinity was confirmed by biosensor measurements. Structural analysis of overlapping peptides revealed increased helicity in the p200 peptide compared to non-recognized peptides, indicating epitope conformation as essential for antibody binding. Both monoclonals produced punctate nuclear and diffuse cytoplasmic staining in human and mouse cell lines. The identified antibodies, which react specifically with the leucine zipper structure of Ro52, will be valuable in further exploration of the mechanisms operating during development of Ro52 antibody-associated congenital heart block.
A method of producing complete heart block (CHB) in open-chest dogs is described. Having found previous methods unreliable in our hands or excessively complex for the acute open-chest setting, we constructed an electrocautery pinch-clamp device that functions in both locating and destroying the area of the atrial septum that contains the atrioventricular node and His bundle. Fifteen male mongrel dogs were anesthetized with alpha-chloralose, intubated, and ventilated (Harvard 607). Through a left thoracotomy at the fifth intercostal space, the two arms of the clamp are introduced into the left and right atria, respectively, via the atrial appendages. The correct site for electrocautery is located by gently squeezing the atrial septum between the arms of the clamp. Systematic testing of the region of the septum that lies, roughly, between the coronary sinus ostium and the anterior portion of the septal leaflet of the tricuspid valve will result in a rhythm disturbance when the correct site is squeezed. Sustained pressure will yield overt dissociation of the atrial and ventricular contractions. The electrocautery current is then activated for 10-15 s. Lead II of the electrocardiogram is monitored, and if CHB is not sustained after 5 min, the procedure is repeated. Once CHB is established, the clamp is removed and the atrial defects are ligated. By application of this method with no prior use of the technique, 12 of 15 attempts produced stable CHB lasting at least 3-4 h. Examination of the hearts of eight of the animals revealed no septal defects or damage to the tricuspid valve. We conclude that this method offers significant advantages for the production of CHB in acute studies in the dog.
Congenital heart block is a serious condition with significant mortality due in most cases to the transplacental transfer of autoantibodies from an otherwise asymptomatic mother. Although SSA/Ro and SSB/La autoantibodies have been implicated, attention has focused recently on autoantibodies to envelope proteins of endogenous retrovirus-3 (ERV-3). We have recently identified in 1% of the caucasian population a natural knock out of ERV-3 due to a premature stop mutation generating a severely truncated form of the protein [corrected]. If a pregnant female homozygous for the truncated form of the ERV-3 carries a foetus expressing the entire protein, the mother might be expected to acquire high titre immunity, while the foetus homozygous for the truncated form would not be expected to immunise its mother. In order to test whether this naturally occurring model could shed light on the pathogenesis of CHB, we determined the status of the ERV-3 stop polymorphism in 12 mothers of CHB infants [corrected]. The fact that none was homozygous for the stop mutation tends to rule out a role for the stop polymorphism of the mothers in the generation of the CHB disease, but does not exclude that other polymorphisms might be involved [corrected].
Lyme disease is a tick-borne spirochetal infection, characterized by erythema chronicum migrans and an acute systemic illness. The disease is endemic in many parts of the north-eastern United States. Without treatment, late rheumatic, neurologic, and cardiac complications frequently occur. We report four serologically confirmed cases of Lyme carditis in previously healthy young men (mean age, 45 years) from endemic areas. Each presented with severe symptomatic atrioventricular block, three with episodes of prolonged ventricular asystole. Two had permanent pacemakers implanted (one was later removed), and another, very nearly did, before diagnosis. All four patients were treated with antibiotics, and in each case their rhythm returned to sinus, though one patient has Wenckebach second degree block with atrial pacing at 120 beats/min 16 months later. Carditis occurs in 4% to 10% of cases of Lyme disease and usually begins 3 to 6 weeks after the initial illness. It manifests as a transient myocarditis with varying degrees of atrioventricular block. The diagnosis is made primarily on clinical grounds and confirmed by serologic testing. Temporary cardiac pacing is frequently needed by patients who have severe heart block with hemodynamic instability. The evidence suggests that, in most cases, the block is at the level of the atrioventricular node. The block generally resolves completely with antibiotic treatment. Complete heart block rarely persists more than 1 week and the long-term prognosis appears to be excellent. Consideration and prompt recognition of this potentially lethal, but reversible, cause of heart block is crucial in order to avoid inappropriate permanent pacemaker implantation.
A 68-year-old woman presented with active rheumatoid arthritis (RA) and severe extra-articular manifestations. During the course of her treatment, her electrocardiogram (ECG) transformed from normal sinus rhythm to left bundle branch block and finally to complete heart block (CHB). Investigations ruled out an ischaemic event. A permanent pacemaker was inserted due to the symptoms of heart failure and she made an uneventful recovery. CHB in RA is probably a marker of severity of the disease.
OBJECTIVE: Neonatal lupus syndrome-congenital heart block (NLS-CHB) is an acquired autoimmune disease in which maternal autoantibodies are necessary but not sufficient for disease. Maternal myocardial cells have been found in the hearts of patients with NLS-CHB, suggesting that maternal microchimerism may also play a role. In this study we asked whether levels of microchimerism in the blood are associated with NLS-CHB in discordant twins and triplets. METHODS: Human leucocyte antigen (HLA)-specific and Y-chromosome-specific real-time quantitative polymerase chain reaction (PCR) was used to quantitatively assay maternal and sibling microchimerism in peripheral blood. Because of HLA allele sharing in families, it was not always possible to distinguish between multiple sources of microchimerism. RESULTS: In one family, maternal and/or sibling microchimerism was detected in two triplets who had CHB, but not in the triplet with transient hepatitis. Levels ranged from 4 to 948 genome-equivalents of foreign deoxyribonucleic acid per million host genome-equivalents (gEq/million). Over the first year levels of sibling microchimerism decreased in the triplet with complete CHB and increased in the triplet who progressed from first- to second-degree CHB. In a second family, maternal and/or sibling microchimerism was detected in the healthy twin (1223 gEq/million) but not in the twin with CHB. CONCLUSIONS: Maternal and/or sibling microchimerism was detectable in the blood of infant twins and triplets discordant for NLS. Microchimerism in the blood was not specific for NLS-CHB, although in one family levels correlated with disease. Thus, microchimerism in the blood and/or tissues may be involved in the pathogenesis or progression of NLS-CHB, but additional factors must also contribute. Further investigation is warranted.
A family is reported in which complete heart block developed late in life, apparently inherited as an autosomal dominant trait. Two octogenarian brothers had symptomatic complete heart block, and their younger relations asymptomatic conduction abnormalities. Neurological disease was present in one proband; investigations suggested that this was a fortuitous association.
We report on two patients out of a series of 22 who underwent transcatheter ablation of the atrioventricular (AV) junction. The procedure failed to induce permanent complete heart block in 15 patients, 12 of whom were in sinus rhythm with 1:1 AV conduction before hospital discharge. Of the 12 patients, two (16.6%) were found to be in high degree heart block, one month later. We discuss the mechanism of late occurrence of high degree heart block and we emphasize the need for systematic implantation of permanent ventricular or dual chamber pacemakers, despite failure of transcatheter ablation of the AV junction.
Two siblings with hypertrophic cardiomyopathy developed spontaneous complete heart block requiring permanent pacemaker implantation at similar ages (29 and 33 years). The clinical, morphological, and haemodynamic expressions of hypertrophic cardiomyopathy differed considerably in these two patients. The sister had severe functional limitation due to dyspnoea, pronounced and diffuse left ventricular hypertrophy (maximum ventricular septal thickness of 41 mm), and left ventricular outflow obstruction (peak subaortic gradient of 75 mm Hg under basal conditions). In contrast the brother was symptom free, had only modest left ventricular hypertrophy which was confined to the anterior ventricular septum (maximal thickness of 16 mm), and had no echocardiographic evidence of subaortic obstruction. These dissimilar findings in siblings with hypertrophic cardiomyopathy suggest that the predisposition to develop complete heart block was probably genetically transmitted, although it was unrelated to the phenotypic and clinical expression of the disease.