Anti-Ro/SSA Antibodies Blocking Calcium Channels as a Potentially Reversible Cause of Atrioventricular Block in Adults

BACKGROUND In similar to 50% of severe atrioventricular blocks (AVBs) occurring in adults <50 years, the underlying etiology remains unknown. Preliminary evidence from case reports suggests that autoimmunity, specifically the presence of circulating anti-Ro/SSA antibodies in the patient (acquired form), in the patient's mother (late-progressive congenital form), or in both (mixed form), could be involved in a fraction of idiopathic AVBs in adults by possibly targeting the L-type calcium channel (Ca(v)1.2) and inhibiting the related current (I-CaL). OBJECTIVES The purpose of this study was to evaluate whether anti-Ro/SSA antibodies are causally implicated in the development of isolated AVBs in adults. METHODS Thirty-four consecutive patients with isolated AVB of unknown origin and 17 available mothers were prospectively enrolled in a cross-sectional study. Anti-Ro/SSA antibodies were assessed by fluoroenzyme-immunoassay, immuno-Western blotting, and line-blot immunoassay. Purified immunoglobulin-G (IgG) from anti-Ro/SSA-positive and anti-Ro/SSA-negative subjects were tested on I-CaL and Ca(v)1.2 expression using tSA201 and HEK293 cells, respectively. Moreover, in 13 AVB patients, the impact of a short course of steroid therapy on AV conduction was evaluated. RESULTS Anti-Ro/SSA antibodies, particularly anti-Ro/SSA-52kD, were found in 53% of AVB-patients and/or in their mothers, most commonly an acquired or mixed form (two-thirds of cases) without history of autoimmune diseases. Purified IgG from anti-Ro/SSA-positive but not anti-Ro/SSA-negative AVB patients acutely inhibited I-CaL and chronically down-regulated Ca(v)1.2 expression. Moreover, anti-Ro/SSA-positive sera showed high reactivity with peptides corresponding to the Ca(v)1.2 channel pore-forming region. Finally, steroid therapy rapidly improved AV conduction in AVB-patients with circulating anti-Ro/SSA antibodies but not in those without. CONCLUSIONS Our study points to anti-Ro/SSA antibodies as a novel, epidemiologically relevant and potentially reversible cause of isolated AVB in adults, via an autoimmune-mediated functional interference with the L-type calcium channels. These findings have significant impact on antiarrhythmic therapies by avoiding or delaying pacemaker implantation. (c) 2023 by the American College of Cardiology Foundation.

Automated summary

This study suggests that anti-Ro/SSA antibodies may be a cause of isolated AVB in adults, potentially by interfering with L-type calcium channels. Steroid therapy can improve AV conduction in patients with these antibodies. These findings have significant implications for the treatment of arrhythmias.