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

Figures

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  Figure 1. Anti-Ro/SSA antibodies, which can inhibit the IKr 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; IKr, 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.

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  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), IKr is preserved, and APD and QTc are normal. In subjects with the sole presence of arrhythmogenic anti-Ro/SSA antibodies partially inhibiting IKr (+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 IKr 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. IKr, rapidly activating component of the delayed outward-rectifying K+ current;…