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Kcne3 deletion initiates extracardiac arrhythmogenesis in mice

  • Author(s): Hu, Z
  • Crump, SM
  • Anand, M
  • Kant, R
  • Levi, R
  • Abbott, GW
  • et al.
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 QTcprolongation 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. © FASEB.

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