Charakterisierung von Autoantikörpern gegen den kardialen repolarisierenden KCNQ1 Kaliumkanal im Kaninchenmodel.
Zusammenfassung der Projektergebnisse
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.
Projektbezogene Publikationen (Auswahl)
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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
