Abstract
Although a strong clinical association exists between congenital heart block (CHB) and an immune response to SSA/Ro and SSB/La proteins, a causative role of these antibodies in the pathogenesis is just emerging. In a preliminary report, we have demonstrated that IgG fractions isolated from the sera of mothers whose children have CHB are arrhythmogenic in the human fetal heart. To more precisely define the arrhythmogenic effect of anti-SSA/Ro-SSB/La antibodies, we used the readily available rat heart model to record: 1) ECGs from Langendorff beating hearts;2) action potentials from atrioventricular (AV) nodal preparations;3) L-type Ca currents, ICa at the whole-cell and single channel levels; and 4) other currents such as the transient outward K+ current,Ito, the inward rectifier K+ current,IK1, and the Na+ current,INa. Perfusion of hearts with purified IgG (800 µg/mL), isolated from the serum of a mother with SSA/Ro and SSB/La antibodies whose child had CHB, resulted in bradycardia associated with 2:1 AV block. Simultaneous action potentials were recorded from dissected atrial and AV nodal areas of the rat heart. Superfusion of these preparations with the same mother's IgG fraction resulted in 2:1 AV block followed by complete inhibition of AV nodal action potential. Because AV nodal electrogenesis is largely dependent on ICa, the effect of these antibodies on ICa was subsequently determined. Superfusion of myocytes with whole serum or purified IgG (80 µg/mL) from the same mother consistently inhibited whole cell ICa, ensemble average Ba2+ currents (IBa) and open state probability, po, without affecting the channel conductance. IgG had no significant effect on Ito,IK1, or INa. Whole sera and IgG fractions from a healthy mother with no detectable anti-SSA/Ro or SSB/La antibodies did not inhibit ICa or IBa. These results demonstrate that IgG containing anti-SSA/Ro and -SSB/La antibodies induces complete AV block in beating hearts and in multicellular preparations, thus implicating a preferential interaction of these autoantibodies with Ca channels and/or associated regulatory proteins. This is consistent with the observed inhibition of Ca channels that may be a critical factor contributing to the pathogenesis of CHB.
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Abbreviations
- AV :
-
atrioventricular
- CHB :
-
congenital heart block
- I Na :
-
sodium current
- I Ca :
-
L-type Ca current
- I to :
-
transient outward K current
- I K1 :
-
inward rectifier K current
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Acknowledgements
The authors thank the animal laboratory staff at the Veterans Administration Medical Center for their technical assistance.
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Supported by National Heart, Lung and Blood Institute Grant HL-55401(M.B.), Veterans Administration Medical Research Funds (M.B.), Grant AR-42455 from the National Institute of Arthritis, Musculoskeletal, and Skin Diseases(J.P.B.), and a grant-in-aid from the American Heart Association, New York Affiliate (J.P.B.).
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Boutjdir, M., Chen, L., Zhang, ZH. et al. Serum and Immunoglobulin G from the Mother of a Child with Congenital Heart Block Induce Conduction Abnormalities and Inhibit L-Type Calcium Channels in a Rat Heart Model. Pediatr Res 44, 11–19 (1998). https://doi.org/10.1203/00006450-199807000-00002
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DOI: https://doi.org/10.1203/00006450-199807000-00002
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