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KCNQ1 Antibodies for Immunotherapy of Long QT Syndrome Type 2

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Author Maguy Ange, Kucera Jan P., Wepfer Jonas P., Forest Virginie, Charpentier Flavien, Li Jin,
Project Understanding the roles of mechanical stretch and of sodium channel nanodomains in cardiac excitation: a multidisciplinary approach
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Original article (peer-reviewed)

Journal Journal of the American College of Cardiology
Volume (Issue) 75(17)
Page(s) 2140 - 2152
Title of proceedings Journal of the American College of Cardiology
DOI 10.1016/j.jacc.2020.02.067

Open Access

Type of Open Access Publisher (Gold Open Access)


Background: Patients with long QT syndrome (LQTS) are predisposed to life-threatening arrhythmias. A delay in cardiac repolarization is characteristic of the disease. Pharmacotherapy, implantable cardioverter-defibrillators, and left cardiac sympathetic denervation are part of the current treatment options, but no targeted therapy for LQTS exists to date. Previous studies indicate that induced autoimmunity against the voltage-gated KCNQ1 Kþ channels accelerates cardiac repolarization. Objectives: However, a causative relationship between KCNQ1 antibodies and the observed electrophysiological effects has never been demonstrated, and thus presents the aim of this study. Methods: The authors purified KCNQ1 antibodies and performed whole-cell patch clamp experiments as well as single channel recordings on Chinese hamster ovary cells overexpressing IKs channels. The effect of purified KCNQ1 antibodies on human cardiomyocytes derived from induced pluripotent stem cells was then studied. Results: The study demonstrated that KCNQ1 antibodies underlie the previously observed increase in repolarizing IKs current. The antibodies shift the voltage dependence of activation and slow the deactivation of IKs. At the single-channel level, KCNQ1 antibodies increase the open time and probability of the channel. In models of LQTS type 2 (LQTS2) using human induced pluripotent stem cell-derived cardiomyocytes, KCNQ1 antibodies reverse the prolonged cardiac repolarization and abolish arrhythmic activities. Conclusions: Here, the authors provide the first direct evidence that KCNQ1 antibodies act as agonists on IKs channels. Moreover, KCNQ1 antibodies were able to restore alterations in cardiac repolarization and most importantly to suppress arrhythmias in LQTS2. KCNQ1 antibody therapy may thus present a novel promising therapeutic approach for LQTS2.