Autoimmune-Associated Congenital Heart Block: Demographics, Mortality, Morbidity and Recurrence Rates Obtained From a National Neonatal Lupus Registry

Buyon, Jill P.; Hiebert, Rudi; Copel, Joshua A.; Craft, Joseph; Friedman, Deborah; Katholi, Margaret; Lee, Lela A.; Provost, Thomas T.; Reichlin, Morris; Rider, Lisa G.; Rupel, Ann; Saleeb, Susan F.; Weston, William L.; Skovron, Mary Louise

doi:10.1016/s0735-1097(98)00161-2

Cited by 680 publications

(650 citation statements)

References 30 publications

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“…Cord blood samples and ELISA for erythropoietin. Cord blood samples were obtained at birth from family members enrolled in the Research Registry for Neonatal Lupus (14) as well as the PR Interval and Dexamethasone Evaluation in CHB Study (15). For inclusion in the present study, a child was considered to have CHB if the following 2 criteria were met: 1) presence of heart block (first-, second-, or third-degree) documented by electrocardiogram, echocardiogram, history of pacemaker, or statement in the medical record; and 2) presence of antibodies to SSA/Ro in the maternal serum, as determined by commercial ELISA (Diamedix, Miami, FL), ELISA with recombinant proteins, and/or SDS immunoblotting to identify the fine specificity of the autoantibody response.…”

Section: Hypoxia Fibrosis and Congenital Heart Block 4123mentioning

confidence: 99%

Role of hypoxia and cAMP in the transdifferentiation of human fetal cardiac fibroblasts: Implications for progression to scarring in autoimmune‐associated congenital heart block

Clancy¹,

Zheng²,

O’Mahony³

et al. 2007

Arthritis & Rheumatism

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Objective. Identification of isolated congenital heart block (CHB) predicts, with near certainty, the presence of maternal anti-SSA/Ro antibodies; however, the 2% incidence of CHB in first offspring of anti-SSA/ Ro؉ mothers, 20% recurrence in subsequent pregnancies, and discordance in identical twins suggest that an environmental factor amplifies the effect of the antibody. Accordingly, this study was carried out to explore the hypothesis that hypoxia potentiates a profibrosing phenotype of the fetal cardiac fibroblast.Methods. Evidence of an effect of hypoxia was sought by immunohistologic evaluation of CHB-affected fetal heart tissue and by determination of erythropoietin levels in cord blood. The in vitro effect of hypoxia on gene expression and phenotype in fibroblasts derived from fetal hearts and lungs was investigated by Affymetrix arrays, quantitative polymerase chain reaction (PCR), immunofluorescence, and immunoblotting.Results. In vivo hypoxic exposure was supported by the prominent intracellular fibroblast expression of hypoxia-inducible factor 1␣ in conduction tissue from 2 fetuses in whom CHB led to death. The possibility that hypoxia was sustained was suggested by significantly elevated erythropoietin levels in cord blood from CHBaffected, as compared with unaffected, anti-SSA/Roexposed neonates. In vitro exposure of cardiac fibroblasts to hypoxia resulted in transdifferentiation to myofibroblasts (a scarring phenotype), as demonstrated on immunoblots and immunofluorescence by increased expression of smooth muscle actin (SMA), an effect not seen in lung fibroblasts. Hypoxia-exposed cardiac fibroblasts expressed adrenomedullin at 4-fold increased levels, as determined by Affymetrix array, quantitative PCR, and immunofluorescence, thus focusing attention on cAMP as a modulator of fibrosis. MDL12,330A, an adenylate cyclase inhibitor that lowers the levels of cAMP, increased expression of fibrosis-related proteins (mammalian target of rapamycin, SMA, plasminogen activator inhibitor type 1, and type I collagen), while the cAMP activator forskolin attenuated transforming growth factor ␤-elicited fibrosing end points in the cardiac fibroblasts.Conclusion. These findings provide evidence that hypoxia may amplify the injurious effects of anti-SSA/Ro antibodies. Modulation of cAMP may be a key component in the scarring phenotype. Further assessment of the susceptibility of cardiac fibroblasts to cAMP modulation offers a new research direction in CHB.Congenital heart block (CHB) which occurs without structural abnormalities and is detectable in the second trimester is almost universally associated with maternal IgG autoantibodies reactive with the intracellular soluble ribonucleoproteins 48-kd SSB/La, 52-kd

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Section: Hypoxia Fibrosis and Congenital Heart Block 4123mentioning

confidence: 99%

Role of hypoxia and cAMP in the transdifferentiation of human fetal cardiac fibroblasts: Implications for progression to scarring in autoimmune‐associated congenital heart block

Clancy¹,

Zheng²,

O’Mahony³

et al. 2007

Arthritis & Rheumatism

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“…The identification of a fetus at risk for developing CHB would be invaluable, given the substantial morbidity (ϳ65% require lifelong pacing) and mortality (ϳ20%) associated with this disease (5,9,(18)(19)(20). Moreover, current echocardiographic technologies are being evaluated for early in utero detection at a time when injury might still be reversible (12,13,(21)(22)(23).…”

Section: Discussionmentioning

confidence: 99%

“…The study included mothers enrolled in the RRNL (9) who had at least 1 child with CHB (and in many cases healthy children as well), and RRNL mothers who had at least 1 child with isolated neonatal lupus rash and no children with CHB. In addition, mothers were recruited from the PRIDE in CHB study, which had 2 aims: to evaluate pregnant women with anti-SSA/Ro antibodies (regardless of pregnancy history) by fetal echocardiography weekly from 16 to 26 weeks and biweekly from 26 to 32 weeks in an attempt to find a reversible marker of fetal cardiac injury, and to evaluate the efficacy of maternal oral dexamethasone (open-label, nonrandomized) in the treatment of an established conduction abnormality (first-, second-, or third-degree block).…”

Section: Methodsmentioning

confidence: 99%

“…To address both the clinical necessity and the sufficiency of this newly identified p200 reactivity in the development of CHB, as well as the reduced risk of CHB reportedly associated with aa176-196 (p176) and aa197-232 (p197) (7), maternal sera from the Research Registry for Neonatal Lupus (RRNL) (9) and the prospective, multicenter study, PR Interval and Dexamethasone Evaluation (PRIDE) in CHB (4) were evaluated. In addition, the PRIDE study provided the opportunity to address whether the level of anti-p200 antibodies correlated positively with the length of the Doppler mechanical PR interval.…”

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confidence: 99%

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Maternal antibody responses to the 52‐kd SSA/RO p200 peptide and the development of fetal conduction defects

Clancy¹,

Buyon²,

Ikeda³

et al. 2005

Arthritis & Rheumatism

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Objective. To identify a finer level of antibody specificity for risk of congenital heart block (CHB) than reactivity to 52-kd SSA/Ro (Ro 52).Methods. Serum from mothers enrolled in the Research Registry for Neonatal Lupus and the observational PR Interval and Dexamethasone Evaluation (PRIDE) study was evaluated for reactivity against peptide aa200-239 of Ro 52 (p200), recently reported to be associated with a higher risk of CHB.Results. The majority of 156 Ro 52-positive sera tested were reactive with p200 (>3 SD above control), irrespective of the clinical status of the child. Optical density (OD) values of p200 did not differ significantly among mothers of children with CHB (mean ؎ SD 0.187 ؎ 0.363), mothers of children with rash (mean ؎ SD 0.176 ؎ 0.356), and mothers of children without neonatal lupus (mean ؎ SD 0.229 ؎ 0.315). Reactivity against p200 was found in 80 of 104 mothers of children with CHB (77%), 24 of 30 mothers of children with rash (80%), and 21 of 22 mothers who delivered healthy children and had no children with neonatal lupus (95%) (P not significant for all comparisons). Sera from 4 mothers of children with CHB with varied p200 titers (OD range 0.025-1.818) bound to the surface of nonpermeabilized apoptotic, but not proliferating, human fetal cardiocytes. In 32 Ro 52-positive women who completed the PRIDE study (22 with no child with neonatal lupus, 7 with a child with CHB, and 3 with a child with rash) in whom p200 levels were determined during pregnancy, the correlation between level of p200 (OD range 0.000-1.170) and maximal fetal PR interval (range 115-168 msec) was not significant ( ‫؍‬ 0.107, P ‫؍‬ 0.58).Conclusion. Reactivity to p200 is a dominant but not uniform anti-Ro 52 response in women whose children have CHB. Since exposure to this antibody specificity was observed with a similar frequency in children without CHB born to mothers with anti-Ro 52, additional factors are necessary to convert risk to disease expression.Accumulated data suggest that women with anti-SSA/Ro antibodies identified by commercial enzymelinked immunosorbent assay (ELISA) face a 2% risk of having a child with neonatal lupus-congenital heart block (CHB), most often third-degree (1). While recent reports suggest that this risk may increase to 5% in the presence of anti-SSB/La antibodies (2), identification of more specific antibody reactivity would be a major advance in the translational approach to CHB. There is a clear need to identify an early marker of CHB, given that established third-degree block has not been reversed to date, despite treatment with maternal steroids known to be effective in the fetal circulation (3). Presently, weekly echocardiographic evaluation of all fetuses exposed to anti-SSA/Ro antibodies has been recommended to detect potentially reversible incomplete blocks (4). The discovery of an antibody specificity that induces injury to the developing human conduction system could lead to treatments directed toward removal

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“…2 Fetuses diagnosed with autoimmune-mediated complete congenital heart block are at risk for developing heart failure, hydrops or fetal demise due to inadequate cardiac output. Many fetuses ultimately require ventricular pacing for poor cardiac output shortly after delivery.…”

Section: Introductionmentioning

confidence: 99%

The cerebroplacental Doppler ratio predicts postnatal outcome in fetuses with congenital heart block

et al. 2008

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Objective: Autoimmune-mediated congenital complete heart block (CCHB) is associated with significant perinatal morbidity and mortality, and prenatal monitoring of these fetuses is a significant challenge. The cerebroplacental Doppler ratio (CPR), defined as the ratio of the middle cerebral artery pulsatility index (MCA-PI) to the umbilical artery pulsatility index (UA-PI), is predictive of perinatal outcome in growth-restricted fetuses. This study tests the hypothesis that the CPR would be useful in monitoring fetal well-being in fetuses with CCHB.Study Design: We reviewed data on all patients diagnosed prenatally with autoimmune-mediated CCHB at our institution over the past 2 years. The fetal echocardiograms from each patient were analyzed for: CPR, UA-PI, MCA-PI, cardiothoracic ratio, degree of tricuspid regurgitation, ventricular function and presence of effusions. We compared hemodynamic data from the fetal echocardiogram before delivery in patients who required urgent pacemaker placement postnatally to those patients that did not require an urgent pacemaker.Result: Five patients with autoimmune-mediated CCHB were identified, and two patients required urgent pacemaker placement. The CPR before delivery was significantly lower in the patients who required urgent pacemaker placement (0.97±0.06 versus 1.45±0.03; P ¼ 0.003), but there was no difference in other fetal echocardiographic markers between groups. Both patients requiring urgent pacemaker placement had a CPR less than 1.08. Conclusion:The CPR is predictive of postnatal outcome in fetuses with CCHB and is useful in prenatal monitoring of these patients.

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Autoimmune-Associated Congenital Heart Block: Demographics, Mortality, Morbidity and Recurrence Rates Obtained From a National Neonatal Lupus Registry

Cited by 680 publications

References 30 publications

Role of hypoxia and cAMP in the transdifferentiation of human fetal cardiac fibroblasts: Implications for progression to scarring in autoimmune‐associated congenital heart block

Role of hypoxia and cAMP in the transdifferentiation of human fetal cardiac fibroblasts: Implications for progression to scarring in autoimmune‐associated congenital heart block

Maternal antibody responses to the 52‐kd SSA/RO p200 peptide and the development of fetal conduction defects

The cerebroplacental Doppler ratio predicts postnatal outcome in fetuses with congenital heart block

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