Characterization of autoantibodies targeting the cardiac repolarizing KCNQ1 potassium channel in a rabbit model.
Final Report Abstract
The cardiac voltage-gated KCNQ1 potassium channel plays a substantial role in ventricular repolarization and arrhythmogenesis. We developed an experimental autoimmune model against KCNQ1 in rabbits to study the electrophysiological effects of anti-KCNQl autoantibodies. Following immunization against KCNQ1, rabbits produced autoantibodies targeting the channel and infiltration of IgG within the myocardium was found. Consistent with results in a previously reported subgroup of patients with dilated cardiomyopathy and KCNQ1 autoantibodies that demonstrated QTc-interval shortening, KCNQl-immunized rabbits developed a shortened QTc interval. During in vivo electrophysiological study, we measured a reduced ventricular effective refractory period. Moreover, cardiomyocytes from KCNQl-immunized rabbits presented action potential duration abbreviation and /Ks potassium current enhancement providing direct experimental support for the presumed pathophysiology underlying the clinical observations. Cardiac function was not substantially affected by KCNQl-immunization as assessed by echocardiography. Histopathological staining of myocardial tissue showed no signs of inflammation or fibrosis thus further supporting the notion of a primary electrical pathomechanism rather than effects secondary to hemodynamic or structural remodeling. Finally, we investigated the therapeutic potential of vaccination against KCNQ1 in a rabbit LQT Syndrome model. KCNQl-immunization attenuated QTc interval prolongation induced by administration of the /Kr-blocker, dofetilide. This project is the first of which we are aware to provide evidence for therapeutic use of vaccination against cardiac ion channels to treat arrhythmias in susceptible patient subgroups.
Publications
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Induced KCNQ1 autoimmunity accelerates cardiac repolarization in rabbits: potential significance in arrhythmogenesis and antiarrhythmic therapy. Heart Rhythm, Volume 11, Issue 11, November 2014, Pages 2092-2100
Li, Jin; Maguy, Ange; Duverger, James Elber; Vigneault, Patrick; Comtois, Philippe; Shi, Yanfen; Tardif, Jean-Claude; Thomas, Dierk & Nattel, Stanley
