Pathogenesis of Autoimmune-Associated Long QT Syndrome

The impact of autoimmunity on the heart electrical activity is being more and more recognized, as clinical and experimental evidences demonstrate the association between the presence of pathogenic autoantibodies and cardiac repolarization. Long QT syndrome (LQTS) which manifests as prolongation of the repolarization measured as QT interval on the surface electrocardiogram, increases risk for ventricular arrhythmia particularly torsades de pointes. Here, we discuss current knowledge in the functional and molecular basis of autoantibody (anti-Ro/SSA antibodies)-induced QTc prolongation in patients with autoimmune diseases particularly connective tissue disease as well as in the general population subjects with torsades de pointes. Specifically, in vitro and in vivo experimental evidence is provided demonstrating that the human Ether-a-go-go-Related Gene, hERG, potassium channel conducting the rapidly activating delayed potassium current, IKr, is a target for anti-Ro/SSA antibodies, leading to action potential duration prolongation and QT interval lengthening on the surface electrocardiogram, thus predisposition to torsades de pointes. The predicted anti-Ro/SSA antibody binding sites have been identified on the hERG extracellular loop between S5/S6, thereby opening new avenues in the development of decoy peptide-based therapeutic approaches.