Background-Congenital heart block (CHB) is an autoimmune disease that affects fetuses/infants born to mothers with anti-Ro/La antibodies (positive IgG). Although the hallmark of CHB is complete atrioventricular block, sinus bradycardia has been reported recently in animal models of CHB. Interestingly, knockout of the neuroendocrine ␣ 1D Ca channel in mice results in significant sinus bradycardia and atrioventricular block, a phenotype reminiscent to that seen in CHB. Here, we tested the hypothesis that the ␣ 1D Ca channel is a novel target for positive IgG.
A novel acquired autoimmune-associated LQTS has been recently reported in adult patients carrying anti-Ro antibodies (anti-Ro Abs), 7-10 which result from an autoimmune response against the intracellular ribonucleoprotein, SSA/Ro antigen (Ro). The detection of circulating anti-Ro Abs is relatively Background-Emerging clinical evidence demonstrates high prevalence of QTc prolongation and complex ventricular arrhythmias in patients with anti-Ro antibody (anti-Ro Ab)-positive autoimmune diseases. We tested the hypothesis that anti-Ro Abs target the HERG (human ether-a-go-go-related gene) K + channel, which conducts the rapidly activating delayed K + current, I Kr , thereby causing delayed repolarization seen as QT interval prolongation on the ECG. Methods and Results-Anti-Ro Ab-positive sera, purified IgG, and affinity-purified anti-52kDa Ro Abs from patients with autoimmune diseases and QTc prolongation were tested on I Kr using HEK293 cells expressing HERG channel and native cardiac myocytes. Electrophysiological and biochemical data demonstrate that anti-Ro Abs inhibit I Kr to prolong action potential duration by directly binding to the HERG channel protein. The 52-kDa Ro antigen-immunized guinea pigs showed QTc prolongation on ECG after developing high titers of anti-Ro Abs, which inhibited native I Kr and crossreacted with guinea pig ERG channel. Conclusions-The data establish that anti-Ro Abs from patients with autoimmune diseases inhibit I Kr by cross-reacting with the HERG channel likely at the pore region where homology between anti-52-kDa Ro antigen and HERG channel is present. The animal model of autoimmune-associated QTc prolongation is the first to provide strong evidence for a pathogenic role of anti-Ro Abs in the development of QTc prolongation. It is proposed that adult patients with anti-Ro Abs may benefit from routine ECG screening and that those with QTc prolongation should receive counseling about drugs that may increase the risk for life-threatening arrhythmias. (QTc prolongation) 7-10 but not with conduction abnormalities (complete atrioventricular block), which is well described in children born to mothers with anti-Ro Abs.13,14 Accordingly, it is assumed that the adult heart does not represent an immunological target for anti-Ro Abs. However, emerging clinical observations suggest that anti-Ro Abs may be arrhythmogenic for the adult heart by causing QT interval prolongation.7-10 Specifically, in a cohort of CTD patients, more than half (58%) of patients with anti-Ro Abs displayed a prolonged QTc, with a mean QTc duration significantly longer in anti-Ro Ab-positive versus anti-Ro Ab-negative patients. 7 In a subsequent study, patients with CTD and anti-Ro Ab showed 5-fold higher incidence of complex ventricular arrhythmias compared with anti-Ro Ab-negative patients.9 Despite this high incidence of QTc prolongation and ventricular arrhythmias in patients with CTD, the pathogenesis of this autoimmuneassociated QTc prolongation in the adult remains poorly understood. Methods Study PopulationSe...
current (ICa-L) in the mouse supraventricular tissue. However, its functional role in the heart is just emerging. We used the ␣1D gene knockout (KO) mouse to investigate the electrophysiological features, the relative contribution of the ␣ 1D Ca 2ϩ channel to the global ICa-L, the intracellular Ca 2ϩ transient, the Ca 2ϩ handling by the sarcoplasmic reticulum (SR), and the inducibility of atrial fibrillation (AF). In vivo and ex vivo ECG recordings from ␣1D KO mice demonstrated significant sinus bradycardia, atrioventricular block, and vulnerability to AF. The wild-type mice showed no ECG abnormalities and no AF. Patch-clamp recordings from isolated ␣1D KO atrial myocytes revealed a significant reduction of ICa-L (24.5%; P Ͻ 0.05). However, there were no changes in other currents such as INa, ICa-T, IK, If, and Ito and no changes in ␣1C mRNA levels of ␣1D KO atria. Fura 2-loaded atrial myocytes showed reduced intracellular Ca 2ϩ transient (ϳ40%; P Ͻ 0.05) and rapid caffeine application caused a 17% reduction of the SR Ca 2ϩ content (P Ͻ 0.05) and a 28% reduction (P Ͻ 0.05) of fractional SR Ca 2ϩ release in ␣1D KO atria. In conclusion, genetic deletion of ␣1D Ca 2ϩ channel in mice results in atrial electrocardiographic abnormalities and AF vulnerability. The electrical abnormalities in the ␣1D KO mice were associated with a decrease in the total ICa-L density, a reduction in intracellular Ca 2ϩ transient, and impaired intracellular Ca 2ϩ handling. These findings provide new insights into the mechanism leading to atrial electrical dysfunction in the ␣1D KO mice. mice; calcium transient; arrhythmia; myocyte THE VOLTAGE-GATED ␣ 1D Ca 2ϩ channel was previously considered to be expressed only in cells of neuroendocrine origin (10). Recent studies (11,15,16,19,26) reported that the ␣ 1D deletion in mice causes sinus bradycardia and various degrees of atrioventricular (AV) block. The evidence presented suggests a critical role of the ␣ 1D Ca 2ϩ channel in diastolic depolarization and in the rate of discharge of the sinoatrial (SA) node. The expression of ␣ 1D Ca 2ϩ channel was demonstrated in the SA node, AV node, and atria, but not in the ventricles of adult hearts (15,20,26). Therefore, deletion of ␣ 1D Ca 2ϩ channel could play an important role in altering the normal activity of the atrium and might also contribute to atrial arrhythmias, such as atrial fibrillation (AF).AF is the most common cardiac arrhythmia, and it is associated with a four-to fivefold increase in the risk of stroke compared with the general population. It affects an estimated 2.2 million adults in the United States (4). Because of its clinical relevance and the lack of an effective therapy, many experimental models of AF have been tested to elucidate the mechanisms of initiation and maintenance of AF. A decreased L-type Ca 2ϩ current (I Ca-L ) density is a common finding and has been reported in several models of AF (23,25).Unlike ventricular cells, a unique property of atrial cells is that both ␣ 1C and ␣ 1D Ca 2ϩ channels contribute to the tota...
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