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.

Keywords: Torsades de Pointes; anti-Ro/SSA antibodies; autoimmune cardiac channelopathies; hERG potassium channel; long QT syndrome; sudden cardiac death.

Figure 1

Anti-Ro/SSA antibodies, which can inhibit the I_Kr current by directly recognizing hERG potassium channel (brownish), are independently associated with an increased risk of marked QTc prolongation in a large cohort of Veterans (white). Abs, Antibodies; I_Kr, rapidly activating component of the delayed outward-rectifying K⁺ current; hERG-K⁺, human ether-à-go-go related gene potassium channel; APD, Action potential duration; QTc, heart rate-corrected QT-interval; OR, odds ratio; CI, confidence interval.

Figure 2

Anti-Ro/SSA-antibodies and the multi-hit theory of long-QT syndrome: given that manifold often-redundant ion channel mechanisms physiologically preserve ventricular APD, hence QTc length (repolarization reserve), many QT-prolonging risk factors (“hits”) need to be concomitantly present in a single patient to induce the marked disruption of ventricular repolarization necessary to the occurrence of life-threatening arrhythmias such as TdP. In the absence of QT-prolonging factors (0), I_Kr is preserved, and APD and QTc are normal. In subjects with the sole presence of arrhythmogenic anti-Ro/SSA antibodies partially inhibiting I_Kr (+1/hit 1), APD/QTc usually slightly/moderately prolongs (or even remains in the normal range, depending on pre-existing genetically-determined repolarization reserve). In these subjects, only the concomitant presence of other genetic or acquired QT-prolonging risk factors further inhibiting I_Kr and/or other key ion currents (such as drugs, electrolyte imbalances, etc.: +2/hit 2, +3/hit 3, etc.), can induce the marked APD/QTc prolongation critically required for TdP occurrence. I_Kr, rapidly activating component of the delayed outward-rectifying K⁺ current; APD, Action potential duration; EADs, early afterdepolarizations; QTc, heart rate-corrected QT-interval; TdP, Torsades de Pointes.