Functional Basis of Sinus Bradycardia in Congenital Heart Block

Abstract

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 Ca 2ϩ , delayed rectifier K ϩ (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. Key Words: L-type calcium current Ⅲ T-type calcium current Ⅲ antibodies Ⅲ congenital heart block C ongenital heart block (CHB), detected at or before birth in a structurally normal heart, is strongly associated with autoantibodies reactive with the intracellular soluble ribonucleoproteins 48-kDa SSB/La, 52-kDa SSA/Ro, and 60-kDa SSA/Ro. 1 CHB is presumed to be due to the transplacental passage of these IgG autoantibodies from the mother into the fetal circulation. 2 In addition to various degree of atrioventricular (AV) block, other neonatal abnormalities affecting the skin, liver, and blood elements are also associated with anti-SSA/Ro and -SSB/La antibodies in the maternal and fetal circulation and are grouped under the heading of neonatal lupus syndromes. 3 To date, complete AV block is irreversible, although varying degrees of block have been noted, and second degree block has on rare occasion reverted to normal sinus rhythm. 4 We have recently reported that perfusion of Langendorff perfused rabbit hearts with IgG from mothers with CHB children (positive IgG) caused sinus bradycardia preceding AV block using surface ECG and optical action potentials. 5

Ca2+ currents in cardiac myocytes: Old story, new insights

“…These auto-antibodies produced a similar decrease in I CaL amplitude in rat ventricular cardiomyocytes (Boutjdir et al, 1998), canine Purkinje myocytes (Qu et al, 2001), and rabbit sinoatrial cells (Hu et al, 2004). Interestingly, I CaT from rabbit sinoatrial cells is also blocked by these antibodies (Hu et al, 2004).…”

Novel Molecular Mechanism Involving α 1D (Cav1.3) L-Type Calcium Channel in Autoimmune-Associated Sinus Bradycardia

“…The causal relationship of positive IgG to autoimmuneassociated sinus bradycardia in CHB has been documented in animal models of CHB 4,5,11 and in clinical settings 7,8 ; however, the underlying molecular mechanism remains unknown. The candidate antigens SSA-Ro and SSB-La are intracellularly located, and there is no convincing evidence that maternal antibodies can cross the sarcolemma of a normal myocyte.…”

“…Indeed, positive IgGsuperfused rat and rabbit hearts and pups from mice injected with positive IgG during pregnancy exhibited profound sinus bradycardia by ECG and optical action potential recordings. 4,6,11 Furthermore, we recently showed that superfusion of spontaneously beating single rabbit SA node myocytes with positive IgG resulted in significant sinus bradycardia as measured by an increase in action potential cycle length. 11 In the present study, we also unexpectedly observed expression of the ␣ 1D Ca channel in the fetal ventricle.…”

“…4,6,11 Furthermore, we recently showed that superfusion of spontaneously beating single rabbit SA node myocytes with positive IgG resulted in significant sinus bradycardia as measured by an increase in action potential cycle length. 11 In the present study, we also unexpectedly observed expression of the ␣ 1D Ca channel in the fetal ventricle. This fetal ventricular expression of the ␣ 1D Ca channel is clinically relevant, because some deaths reported in children with CHB are related to heart failure.…”

Impaired Ca2+ homeostasis is associated with atrial fibrillation in the α1D L-type Ca2+ channel KO mouse

“…Whole cell configuration of the patchclamp technique was used for ion current recordings. Cells were first superperfused with Tyrode solution, and then the perfusion was switched to the appropriate solution for each current studied as previously described (7). All experiments were conducted at room temperature.…”