Abstract 13143: KvLQT1 Autoantibodies Accelerate Repolarization and Increase Susceptibility to Ventricular Tachyarrhythmias in an Experimental Model
Introduction: Emerging data indicate the potential involvement of autoantibodies in the pathogenesis of cardiac arrhythmias. In a previous clinical study enrolling patients with dilated cardiomyopathy, we provided the first evidence suggesting that autoantibodies might target the cardiac voltage-gated potassium channel subunit, KvLQT1. Moreover, these immunoglobulins were associated with an accelerated cardiac repolarization as indicated by a shortened QT interval on ECG as well as an increased slow delayed rectifier current (IKs) in HEK 293 cells following exposure to antibody positive patient serum. In order to understand the pathophysiology of KvLQT1 autoimmunity, we developed an experimental autoimmune animal model.
Methods & Results: New Zealand White Rabbits were immunized 1 (n = 6 rabbits), 2 (n = 12 rabbits) or 3 (n = 10 rabbits) times at 1-week intervals with an extracellular peptide sequence of the KvLQT1 channel to induce anti-KvLQT1 autoantibodies, while control (CTL) animals received vehicle injections (n = 14). Surface ECGs disclosed T-wave abnormalities and significantly shortened corrected QT intervals in immunized subjects vs. CTLs (eg. 3x immunization 142 ± 2 vs. CTL 135 ± 2 ms; p = 0.005). In vivo electrophysiological study revealed dose-related decreases in ventricular effective refractory period in immunized rabbits versus CTL animals (Panel A). Moreover, a dose-related increased susceptibility to ventricular tachyarrhythmias was also evidenced by programmed ventricular stimulation (eg. 3x immunization 70% vs. CTL 0%; p = 0.009; Panel B).
Conclusions: Our findings suggest a dose-related arrhythmogenicity of KvLQT1 autoantibodies through acceleration of ventricular repolarization. The present study provides a mechanistic basis for clinical observations of QT-shortening associated with KvLQT1 autoantibodies, supporting the notion of autoimmune-induced short QT syndrome as a novel arrhythmogenic cardiac disease entity.
- © 2013 by American Heart Association, Inc.