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• W2043841716 abstract "Mutations in the human KCNE3 potassium channel ancillary subunit gene are associated with life-threatening ventricular arrhythmias. Most genes underlying inherited cardiac arrhythmias, including KCNE3, are not exclusively expressed in the heart, suggesting potentially complex disease etiologies. Here we investigated mechanisms of KCNE3-linked arrhythmogenesis in Kcne3-/- mice using real-time qPCR, echo- and electrocardiography, ventricular myocyte patch-clamp, coronary artery ligation/reperfusion, blood analysis, cardiac synaptosome exocytosis, microarray and pathway analysis, and multitissue histology. Kcne3 transcript was undetectable in adult mouse atria, ventricles, and adrenal glands, but Kcne3-/- mice exhibited 2.3-fold elevated serum aldosterone (P= 0.003) and differentially expressed gene networks consistent with an adrenal-targeted autoimmune response. Furthermore, 8/8 Kcne3-/- mice vs. 0/8 Kcne3+/+ mice exhibited an activated-lymphocyte adrenal infiltration (P=0.0002). Kcne3 deletion also caused aldosterone-dependent ventricular repolarization delay (19.6% mean QTc prolongation in females; P<0.05) and aldosterone-dependent predisposition to postischemia arrhythmogenesis. Thus, 5/11 Kcne3-/- mice vs. 0/10 Kcne3+/+ mice exhibited sustained ventricular tachycardia during reperfusion (P<0.05). Kcne3 deletion is therefore arrhythmogenic by a novel mechanism in which secondary hyperaldosteronism, associated with an adrenal-specific lymphocyte infiltration, impairs ventricular repolarization. The findings highlight the importance of considering extracardiac pathogenesis when investigating arrhythmogenic mechanisms, even in inherited, monogenic channelopathies.—Hu, Z., Crump, S. M., Anand, M., Kant, R., Levi, R., Abbott, G. W. Kcne3 deletion initiates extracardiac arrhythmogenesis in mice. FASEB J. 28, 935–945 (2014). www.fasebj.org" @default.
• W2043841716 created "2016-06-24" @default.
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• W2043841716 date "2013-11-13" @default.
• W2043841716 modified "2023-10-15" @default.
• W2043841716 title "<i>Kcne3</i> deletion initiates extracardiac arrhythmogenesis in mice" @default.
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• W2043841716 doi "https://doi.org/10.1096/fj.13-241828" @default.
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