Investigative methods of congenital complete heart block

Hamilton, Robert M.; Lee-Poy, Michael; Kruger, Kurt; Silverman, Earl D.

doi:10.1016/s0022-0736(98)80035-6

Cited by 10 publications

(7 citation statements)

References 12 publications

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“…Affinity -purified anti-Ro52 antibodies induced the same effects, showing the individual pathogenic potential of anti-Ro52 anti-bodies. Similar results were obtained in Langendorff-perfused rabbit hearts exposed to anti-Ro/La antibodies purified from mothers of children with CHB [51,52]. Evidence for the pathogenicity of anti-Ro/La antibodies in vivo has been gathered from animal models based on passive transfer of antibodies or active immunization of females before gestation (Table 1) and is reviewed below.…”

Section: Clues To Congenital Heart Block Pathogenic Mechanisms From Esupporting

confidence: 55%

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

Ambrosi

Wahren‐Herlenius

2012

Arthritis Res Ther

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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.

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Section: Clues To Congenital Heart Block Pathogenic Mechanisms From Esupporting

confidence: 55%

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

Ambrosi

Wahren‐Herlenius

2012

Arthritis Res Ther

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“…To accomplish this objective we applied selective calcium channel blockers and pacemaker current ( I f ) blockers to newborn and adult rabbit Langendorff hearts and measured Wenckebach cycle length (WBCL) by examining the effects of decremental atrial pacing on the P-R interval and AV-conduction block. We have used this method previously to demonstrate that WBCL prolongation occurs with perfusion of sera from mothers of children with CHB, but not in the presence of sera from mothers of unaffected children [57]. We have also used this method previously to establish a greater sensitivity to AV block in newborn versus adult rabbit Langendorff hearts upon perfusion of sera from mothers of children with CHB (RM Hamilton, unpublished observations).…”

Section: Resultsmentioning

confidence: 99%

“…The animals were housed in the Animal Care Facility at the Hospital for Sick Children and maintained in accordance with hospital regulations and CCAC guidelines. Rabbit hearts were prepared for perfusion as previously described [57]. Briefly, following loss of the pain reflex, the rabbit sternum was incised and removed.…”

Section: Methodsmentioning

confidence: 99%

“…In order to compare calcium channel blocker effects on newborn versus mature AV nodal conduction, the rabbit Langendorff heart model was modified by atrial pacing the preparation at sequentially shorter cycle lengths until the AV nodal Wenckebach cycle length (WBCL) was identified, as described previously [57]. At baseline and 15 minutes following equilibration of each concentration of channel blocker, the atrium was paced at incrementally faster rates to determine WBCL.…”

Section: Methodsmentioning

confidence: 99%

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Congenital Heart Block Maternal Sera Autoantibodies Target an Extracellular Epitope on the α1G T-Type Calcium Channel in Human Fetal Hearts

et al. 2013

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BackgroundCongenital heart block (CHB) is a transplacentally acquired autoimmune disease associated with anti-Ro/SSA and anti-La/SSB maternal autoantibodies and is characterized primarily by atrioventricular (AV) block of the fetal heart. This study aims to investigate whether the T-type calcium channel subunit α1G may be a fetal target of maternal sera autoantibodies in CHB.Methodology/Principal FindingsWe demonstrate differential mRNA expression of the T-type calcium channel CACNA1G (α1G gene) in the AV junction of human fetal hearts compared to the apex (18–22.6 weeks gestation). Using human fetal hearts (20–22 wks gestation), our immunoprecipitation (IP), Western blot analysis and immunofluorescence (IF) staining results, taken together, demonstrate accessibility of the α1G epitope on the surfaces of cardiomyocytes as well as reactivity of maternal serum from CHB affected pregnancies to the α1G protein. By ELISA we demonstrated maternal sera reactivity to α1G was significantly higher in CHB maternal sera compared to controls, and reactivity was epitope mapped to a peptide designated as p305 (corresponding to aa305–319 of the extracellular loop linking transmembrane segments S5–S6 in α1G repeat I). Maternal sera from CHB affected pregnancies also reacted more weakly to the homologous region (7/15 amino acids conserved) of the α1H channel. Electrophysiology experiments with single-cell patch-clamp also demonstrated effects of CHB maternal sera on T-type current in mouse sinoatrial node (SAN) cells.Conclusions/SignificanceTaken together, these results indicate that CHB maternal sera antibodies readily target an extracellular epitope of α1G T-type calcium channels in human fetal cardiomyocytes. CHB maternal sera also show reactivity for α1H suggesting that autoantibodies can target multiple fetal targets.

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“…Experimental studies conducted in animal models have demonstrated that induction of acute effects in animal models via antiRo/La perfusion on denervated hearts (Langendorffperfused hearts) caused bradycardia. 35,[38][39][40][41] However, none of the clinical and experimental findings clarifies the underlying cause of bradycardia. The AV node is crucial for the genesis and propagation of the electric impulse into ventricles.…”

Section: -37mentioning

confidence: 99%

Neonatal molecular pathologies induced by maternal anti-Ro and anti-La antibodies

Herrera‐Esparza

Avalos‐Díaz

2015

IJRCI

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Investigative methods of congenital complete heart block

Cited by 10 publications

References 12 publications

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

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

Congenital Heart Block Maternal Sera Autoantibodies Target an Extracellular Epitope on the α1G T-Type Calcium Channel in Human Fetal Hearts

Neonatal molecular pathologies induced by maternal anti-Ro and anti-La antibodies

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