Provocation of an autoimmune response to cardiac voltage-gated sodium channel NaV1.5 induces cardiac conduction defects in rats

Sevil Korkmaz, Edgar Zitron, Anna Bangert, Claudia Seyler, Shiliang Li, Peter Hegedüs, Daniel Scherer, Jin Li, Thomas Fink, Patrick A. Schweizer, Evangelos Giannitsis, Matthias Karck, Gábor Szabó, Hugo A. Katus, Ziya Kaya

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Abstract

Objectives This study sought to test the hypothesis that inducing an autoimmune response against the cardiac sodium channel (NaV1.5) induces arrhythmias. Background Sporadic evidence supports the concept that autoantibodies may cause cardiac arrhythmias but substantial experimental investigations using in vivo models have been lacking to date. The Na V1.5 is essential for cardiac impulse propagation and its dysfunction has been linked to conduction disease. Methods Rats were immunized with a peptide sequence derived from the third extracellular loop of the first domain of NaV1.5. After 28 days, we evaluated in vivo both the electrical and mechanical parameters of cardiac function. Histopathology, myocardial gene and protein expression were assessed. Whole-cell patch-clamp was used to measure sodium current (INa) density in isolated cardiomyocytes. Results NaV1.5-immunized rats had high titers of autoantibodies against NaV1.5. On ECG recording, NaV1.5-immunized animals showed significantly prolonged PR-intervals. During Holter ECG-monitoring we observed repeated prolonged episodes of third-degree atrioventricular and sinoatrial block in every NaV1.5-immunized animal, but not in controls. Immunization had no effect on cardiac function. In comparison to controls, myocardial NaV1.5 mRNA and protein levels were decreased in immunized rats. INa density was reduced in cardiomyocytes incubated with sera from NaV1.5-immunized rats and from patients with idiopathic atrioventricular block (AVB) in comparison to sera from respective controls. In patients with idiopathic AVB, we observed autoantibodies against Na V1.5 that were absent in sera from healthy controls. Conclusions Provocation of an autoimmune response against NaV1.5 induces conductance defects probably caused by a reduced expression level and an inhibition of NaV1.5 by autoantibodies, resulting in decreased I Na.

Original languageEnglish
Pages (from-to)340-349
Number of pages10
JournalJournal of the American College of Cardiology
Volume62
Issue number4
DOIs
Publication statusPublished - júl. 23 2013

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ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Korkmaz, S., Zitron, E., Bangert, A., Seyler, C., Li, S., Hegedüs, P., Scherer, D., Li, J., Fink, T., Schweizer, P. A., Giannitsis, E., Karck, M., Szabó, G., Katus, H. A., & Kaya, Z. (2013). Provocation of an autoimmune response to cardiac voltage-gated sodium channel NaV1.5 induces cardiac conduction defects in rats. Journal of the American College of Cardiology, 62(4), 340-349. https://doi.org/10.1016/j.jacc.2013.04.041