Utility of Cardiac Monitoring in Fetuses at Risk for Congenital Heart Block

Friedman, Deborah; Kim, Mimi Y.; Copel, Joshua A.; Davis, C. J.; Phoon, Colin K.L.; Glickstein, Julie S.; Buyon, Jill P.

doi:10.1161/circulationaha.107.707661

Cited by 274 publications

(134 citation statements)

References 40 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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“…Eight foetuses had signs of 1st degree block. It is of note that the cut-offs for 1st degree block were lower than those reported by Friedman [29]. One of these foetuses (whose PR interval was abnormal in the Swedish study but would not have been considered abnormal in the US study) had progression to complete block, and another showed recovery from 2nd degree block to 1st degree block, with betamethasone treatment.…”

Section: Assessment Of First Degree Av Block In Uteromentioning

confidence: 55%

“…Also, the American group did not find any prolongation of QT interval in a prospective study of 98 infants, but in this study, a control group was lacking [29]. Thus, overall, QT prolongation as a consequence of autoantibody injury remains unproven.…”

Section: Qt Interval Prolongationmentioning

confidence: 56%

“…The American group have evaluated the mechanical PR interval [29]. By using the gated-pulsed Doppler technique, time intervals from the onset of the mitral A wave (atrial systole) to the onset of the aortic pulsed Doppler tracing (ventricular systole) within the same left ventricular cardiac cycle may be measured.…”

Section: Assessment Of First Degree Av Block In Uteromentioning

confidence: 99%

“…The authors concluded that prolongation of the PR interval was uncommon and did not precede more advanced block and that advanced block and cardiomyopathy can occur within 1 week of a normal echocardiogram without initial 1st degree block. Echodensities and moderate ⁄ severe tricuspid regurgitation merit attention as early signs of injury [29].…”

Section: Assessment Of First Degree Av Block In Uteromentioning

confidence: 99%

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Arrhythmias Presenting in Neonatal Lupus

Brucato

Previtali

Ramoni

et al. 2010

Scandinavian Journal of Immunology

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Arrhythmogenicity and electrophysiological effects of anti-Ro ⁄ SSA antibodiesBased on the facts that there is no convincing evidence that maternal antibodies can cross the sarcolemma of a normal cardiac myocyte, essentially two major categories of mechanisms for congenital complete heart block (CHB) can be identified. The first is abnormal surface expression of intracellular SSA ⁄ Ro and SSB ⁄ La antigens, eventually induced by apoptosis [1, 2], viral infection [3], UV light and IFNc treatment [4]. The other mechanism is the cross-reactivity of maternal antibodies with targets other than SSA ⁄ Ro and SSB ⁄ La antigens. Maternal antibodies were reported to cross-react with laminin and with human cardiac myosin heavy chain at a critical stage during foetal cardiac development [5,6], but the L-type calcium channels seem particularly important in this hypothesis [7][8][9][10].After preliminary reports, [11,12] Boutjdir in an outstanding paper [7] showed that IgG-enriched fractions and anti-52-kD SSA ⁄ Ro antibodies affinity-purified from the sera of mothers whose children have CHB reversibly induce complete atrioventricular (AV) block in the human foetal heart perfused by the Langendorff technique. At 33 min of perfusion, complete AV block was observed with the presence of only P waves and missing QRS complexes. Reperfusion of the heart with antibodyfree Tyrode's solution for 48 min resulted in partial and slow recovery. Superfusion of hearts with IgG fractions from mothers with affected children also induced bradycardia and AV dissociation. In contrast, IgG from control mothers did not have any measurable effect on AV conduction. In the same paper, the authors showed that anti-Ro ⁄ SSA antibodies inhibit L-type Ca 2+ currents at the whole-cell and single-channel level. Immunization of female BALB ⁄ c mice with recombinant 52-kD SSA ⁄ Ro protein generated high-titre antibodies that crossed the placenta during pregnancy and were associated with varying degrees of AV conduction abnormalities, including complete AV block, in the pups. These findings suggest that anti-52-kD SSA ⁄ Ro antibodies are causally related to the development of CHB.The same group reported that the passive transfer of human anti-Ro/SSA into pregnant mice induced AbstractPerfusion of human foetal heart with anti-Ro ⁄ SSA antibodies induces transient heart block. Anti-Ro ⁄ SSA antibodies may cross-react with T-and L-type calcium channels, and anti-p200 antibodies may cause calcium to accumulate in rat heart cells. These actions may explain a direct electrophysiological effect of these antibodies. Congenital complete heart block is the more severe manifestation of so-called ''Neonatal Lupus''. In clinical practice, it is important to distinguish in utero complete versus incomplete atrioventricular (AV) block, as complete AV block to date is irreversible, while incomplete AV block has been shown to be potentially reversible after fluorinated steroid therapy. Another issue is the definition of congenital AV block, as cardiologists have considered co...

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Lupus Erythematosus

Goodfield,

Dutz,

McCourt

2016

Rook's Textbook of Dermatology, Ninth Edition

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Lupus erythematosus (LE) is a complex spectrum of disease, involving one or multiple organ systems, and characterized by humoral and cellular autoimmunity, resulting in combinations of skin, joint, vascular and internal organ involvement. Skin disease occurs in the overwhelming majority of patients, and the patterns of skin involvement form an important part of subclassification, with localized discoid lupus usually being a single‐system manifestation, and acute cutaneous LE part of a potentially fatal multisystem disease. Intermediate forms, including subacute cutaneous LE are common and variable in their involvement of other organ systems. Ultraviolet exposure is an important disease precipitant. LE forms a major part of the group of disorders called connective tissue diseases, along with systemic sclerosis, localized and generalized morphoea, dermatomyositis, rheumatoid arthritis and Sjögren syndrome on the basis of clinical, pathological and immunological overlap.

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Utility of Cardiac Monitoring in Fetuses at Risk for Congenital Heart Block

Cited by 274 publications

References 40 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

Arrhythmias Presenting in Neonatal Lupus

Lupus Erythematosus

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