Functional basis of sinus bradycardia in congenital heart block.
ABSTRACT Congenital heart block (CHB) is a conduction abnormality characterized by complete atrioventricular (AV) block. CHB affects fetuses and/or newborn of mothers with autoantibodies reactive with ribonucleoproteins 48-kDa SSB/La, 52-kDa SSA/Ro, and 60-kDa SSA/Ro. We recently established animal models of CHB and reported, for the first time, significant sinus bradycardia preceding AV block. This unexpected observation implies that the spectrum of conduction abnormalities extends beyond the AV node to also affect the SA node. To test this hypothesis, we investigated the functional basis of this sinus bradycardia by characterizing the effects of antibodies from mothers with CHB children (positive IgG) on ionic currents that are known to significantly contribute to spontaneous pacing in SA node cells. We recorded L- (I(Ca.L)) and T- (I(Ca.T)) type Ca2+, delayed rectifier K+ (I(K)), hyperpolarization-activated (I(f)) currents, and action potentials (APs) from young rabbit SA node cells. We demonstrated that positive IgG significantly inhibited both I(Ca.T) and I(Ca.L) and induced sinus bradycardia but did not affect I(f) and I(K). Normal IgG from mothers with healthy children did not affect all the currents studied and APs. These results establish that IgG from mothers with CHB children causes substantial inhibition of I(Ca.T) and I(Ca.L), two important pacemaker currents in rabbit SA node cells and point to both I(Ca.T) and I(Ca.L) as major players in the ionic mechanism by which maternal antibodies induce sinus bradycardia in CHB. These novel findings have important clinical significance and suggest that sinus bradycardia may be a potential marker in the detection and prevention of CHB. The full text of this article is available online at http://circres.ahajournals.org
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ABSTRACT: Congenital heart block is considered a model of passively acquired autoimmune disease in which the mother generates anti-SSA/Ro and/or anti-SSB/La antibodies that cross the placenta and presumably injure the heart of developing fetus. CHB is accompanied by ECG abnormalities including AV block, sinus bradycardia, and ventricular dysfunction. Our previous data indicate that these abnormalities are caused by maternal autoantibody-mediated disturbance of L-type Ca channels. To investigate the consequence of chronic exposure of L-type Ca channels in newborn pups to maternal autoantibodies during pregnancy, we immunized female rabbits with human 52 kDa-SSA/Ro (Ro52) recombinant protein. ECG revealed that pups from the immunized group had varying degrees of conduction defects. In addition, I(CaL) density and protein were reduced in hearts of pups from the immunized group. Sera and purified IgG from immunized rabbits inhibited I(Ba) recorded from oocytes with expressed alpha(1C) and beta(2a) subunits of L-type Ca channel. Pups born to Ro52 immunized mothers exhibited down-regulation of L-type calcium channels in heart. The data provide new insight into the pathogenesis of congenital heart block.The FASEB Journal 08/2001; 15(9):1539-45. · 5.70 Impact Factor
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ABSTRACT: In this study, IgG fractions from sera of SLE patients with anti-Ro/SSA or anti-Ro/SSA and anti-La/SSB activity were tested in Langendorff preparations of adult rabbit hearts, aiming to reproduce the cardiac manifestations observed in neonatal lupus in an experimental model. The hearts were perfused with normal Tyrode's solution for 30 min, followed by perfusion with Tyrode's containing 0.3 mg/ml of anti-Ro/SSA- (or anti-Ro/La-) positive IgG (nine sera), anti-ribonucleoprotein (RNP)-positive IgG (five sera), or IgG fractions from normal donors (five sera). In one third of the experiments done with anti-Ro/La-positive IgG, heart block was observed. With the remaining fractions, a decrease in heart rate of 17.1% was observed, but normal sinus rhythm was maintained. The IgG fractions with anti-RNP activity (five experiments) and from normal sera (six experiments) reduced heart rates by 12.9 and 3.3%, respectively, but heart block was not observed. To further characterize the cellular mechanisms involved in the conduction disturbances observed in the whole rabbit hearts, we conducted experiments with ventricular myocytes isolated from young rabbit hearts, studied by whole cell patch-clamp technique. In these experiments, the slow inward currents were analyzed during the superfusion of the cell with normal Tyrode's solution and 5 min after superfusion with Tyrode's solution containing 0.3 mg/ml of anti-Ro/SSA- (or anti-Ro/La-) positive IgG (five sera), anti-RNP-positive IgG (three sera), or IgG from normal donors (four sera). Resting and action potential amplitudes were not affected by any of the sera used. The anti-Ro/SSA IgG fraction induced a mean reduction in the peak slow inward current of 31.6%. IgG fractions with anti-RNP activity reduced slow inward current by 4.4%, whereas IgG fractions from normal donors increased this current by 3.3%. IgG-free fractions from sera of patients with anti-Ro/SSA activity did not alter the peak slow inward current. These results show, for the first time, that the presence of anti-Ro/SSA or anti-Ro/SSA and anti-La/SSB antibody activity in IgG fractions from lupus patients' sera can induce cardiac conduction disorders similar to those observed in neonatal lupus.Journal of Clinical Investigation 03/1994; 93(2):718-24. · 12.81 Impact Factor
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ABSTRACT: It is a widely held view that congenital heart block (CHB) is caused by the transplacental transfer of maternal autoantibodies (anti-SSA/Ro and/or anti-SSB/La) into the fetal circulation. To test this hypothesis and to reproduce human CHB, an experimental mouse model (BALB/c) was developed by passive transfer of human autoantibodies into pregnant mice. Timed pregnant mice (n=54) were injected with a single intravenous bolus of purified IgG containing human anti-SSA/Ro and anti-SSB/La antibodies from mothers of children with CHB. To parallel the "window period" of susceptibility to CHB in humans, 3 groups of mice were used: 8, 11, and 16 days of gestation. Within each group, we tested 10, 25, 50, and 100 microg of IgG. At delivery, ECGs were recorded and analyzed for conduction abnormalities. Bradycardia and PR interval were significantly increased in 8-, 11-, and 16-day gestational groups when compared with controls (P<0.05). QRS duration was not significantly different between all groups. Antibody levels measured by ELISA in both mothers and their offspring confirmed the transplacental transfer of the human antibodies to the pups. The passive transfer model demonstrated bradycardia, first-degree but not complete atrioventricular block in pups. The greater percentage and degree of bradycardia and PR prolongation in the 11-day mouse group correlates with the "window period" of susceptibility observed in humans. The high incidence of bradycardia suggests possible sinoatrial node involvement. All together, these data provide relevant insights into the pathogenesis of CHB.Circulation 04/1999; 99(14):1914-8. · 15.20 Impact Factor