Anti-Ro/SSA Antibodies and the Autoimmune Long-QT Syndrome

Abstract

Autoimmunity is increasingly recognized as a novel pathogenic mechanism for cardiac arrhythmias. Several arrhythmogenic autoantibodies have been identified, cross-reacting with different types of surface proteins critically involved in the cardiomyocyte electrophysiology, primarily ion channels (autoimmune cardiac channelopathies). Specifically, some of these autoantibodies can prolong the action potential duration leading to acquired long-QT syndrome (LQTS), a condition known to increase the risk of life-threatening ventricular arrhythmias, particularly Torsades de Pointes (TdP). The most investigated form of autoimmune LQTS is associated with the presence of circulating anti-Ro/SSA-antibodies, frequently found in patients with autoimmune diseases (AD), but also in a significant proportion of apparently healthy subjects of the general population. Accumulating evidence indicates that anti-Ro/SSA-antibodies can markedly delay the ventricular repolarization via a direct inhibitory cross-reaction with the extracellular pore region of the human-ether-a-go-go-related (hERG) potassium channel, resulting in a higher propensity for anti-Ro/SSA-positive subjects to develop LQTS and ventricular arrhythmias/TdP. Recent population data demonstrate that the risk of LQTS in subjects with circulating anti-Ro/SSA antibodies is significantly increased independent of a history of overt AD, intriguingly suggesting that these autoantibodies may silently contribute to a number of cases of ventricular arrhythmias and cardiac arrest in the general population. In this review, we highlight the current knowledge in this topic providing complementary basic, clinical and population health perspectives.

Case report: A 56-year-old woman presenting with torsades de pointes and cardiac arrest associated with levosimendan administration and underlying congenital long QT syndrome type 1

“…However, congenital LQTS is relatively rare, as reported. Conversely, acquired LQTS is rather common, most frequently associated with electrolyte imbalances, medications, heart failure, structural heart diseases, and, more recently, inflammation and autoimmunity [ [1] , [2] , [3] , [4] ]. Some specific medications account for a substantial part of those [ 14 ].…”

“…TdP, a rare but potentially lethal polymorphic ventricular tachycardia, is characterized by wide QRS complexes of gradually varying amplitude that appear to ‘twist’ around the isoelectric baseline on the electrocardiogram [ 1 ]. It is widely known that TdP is associated with the prolongation of QTc which may be congenital or acquired in the clinical setting of electrolyte disturbances, medication, cardiac disease, cerebrovascular injury, thyroid dysfunction, hypothermia, inflammation, autoimmunity, and many other factors [ [1] , [2] , [3] ]. Certain drugs, like class III antiarrhythmic drugs, antidepressants, and antibiotics, may induce QTc prolongation and TdP [ 4 ].…”

Pathophysiology of Cav1.3 L-type calcium channels in the heart

“…Autoimmune diseases provide an additional level of insight into the development of cardiovascular diseases since autoantibodies have been found to modulate cardiac electrophysiological activity ( Qu et al, 2019 ). Voltage-gated L-type Ca 2+ channels, specifically Ca v 1.3, play a key role in the pathophysiology of cardiac arrhythmias in the presence of autoimmune antibodies such as anti-Ro/SSA and anti-La/SSB ( Qu et al, 2019 ; Lazzerini et al, 2021 ). In particular, the anti-Ro/SSA antibodies interact with Ca v 1.3 through a mechanism of direct channel inhibition ( Qu et al, 2005a ; Lazzerini et al, 2018 ; Qu et al, 2019 ).…”

The Spectrum of Extraglandular Manifestations in Primary Sjögren’s Syndrome

“…The 5-HT4 serotoninergic receptor, the α1C and the α1D subunits of the L-type calcium channel, and the T-type calcium channel are in vitro fetus proteins that may be cross-reactive targets for anti-Ro 52 antibodies of women with pSS [ 271 ]. Thus, the arrhythmogenic effects of anti-Ro52 antibodies and their direct effect on fetus cardiocyte function were correlated with the inhibition of membrane calcium channels [ 272 ].…”