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

卷:62

Article

Korkmaz, Sevil^1,2  Zitron, Edgar^2,3  Bangert, Anna^2,3  Seyler, Claudia^2,3  Li, Shiliang^1,2  Hegedues, Peter^1,2  Scherer, Daniel^2,3  Li, Jin^2,3  Fink, Thomas^2,3  Schweizer, Patrick A.^2,3  Giannitsis, Evangelos^2,3  Karck, Matthias^1,2  Szabo, Gabor^1,2  Katus, Hugo A.^2,3  Kaya, Ziya^2,3 

[1] Heidelberg Univ, Dept Cardiac Surg, D-69120 Heidelberg, Germany

[2] Heidelberg Univ, DZHK German Ctr Cardiovasc Res, Partner Site Heidelberg Mannheim, D-69120 Heidelberg, Germany

[3] Heidelberg Univ, Dept Internal Med 3, D-69120 Heidelberg, Germany

关键词: autoantibodies;    autoimmunity;    cardiac sodium channel;    conduction defect;   

DOI  :  10.1016/j.jacc.2013.04.041

来源: Elsevier

【 摘 要 】

Objectives This study sought to test the hypothesis that inducing an autoimmune response against the cardiac sodium channel (Na(V)1.5) 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(V)1.5 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 Na(V)1.5. 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 (I-Na) density in isolated cardiomyocytes. Results Na(V)1.5-immunized rats had high titers of autoantibodies against Na(V)1.5. On ECG recording, Na(V)1.5-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 Na(V)1.5-immunized animal, but not in controls. Immunization had no effect on cardiac function. In comparison to controls, myocardial Na(V)1.5 mRNA and protein levels were decreased in immunized rats. I-Na density was reduced in cardiomyocytes incubated with sera from Na(V)1.5-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(V)1.5 that were absent in sera from healthy controls. Conclusions Provocation of an autoimmune response against Na(V)1.5 induces conductance defects probably caused by a reduced expression level and an inhibition of Na(V)1.5 by autoantibodies, resulting in decreased I-Na. (C) 2013 by the American College of Cardiology Foundation

【 授权许可】

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