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Updated: May 6, 2026
Isolation and Kv Channel Recordings in Murine Atrial and Ventricular Cardiomyocytes
Published on: March 12, 2013
Kcne3 deletion initiates extracardiac arrhythmogenesis in mice
Zhaoyang Hu1, Shawn M Crump, Marie Anand
11360 Medical Surge II, Department of Pharmacology, School of Medicine, University of California, Irvine, CA 92697, USA. abbottg@uci.edu.
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.
Insights
Mutations in the KCNE3 gene cause dangerous heart arrhythmias. This study reveals a novel mechanism involving adrenal autoimmunity and hyperaldosteronism, leading to ventricular repolarization delay and increased arrhythmia risk.
Area of Science:
- Cardiovascular Research
- Genetics
- Immunology
Background:
- Mutations in the KCNE3 potassium channel gene are linked to ventricular arrhythmias.
- Cardiac channelopathies often involve genes with non-cardiac expression, suggesting complex disease mechanisms.
Purpose of the Study:
- To investigate the arrhythmogenic mechanisms of KCNE3 gene mutations.
- To explore the role of extracardiac factors in KCNE3-linked arrhythmogenesis.
Main Methods:
- Utilized Kcne3 knockout mice for comprehensive analysis.
- Employed techniques including qPCR, echocardiography, electrocardiography, patch-clamp, histology, and gene expression analysis.
Main Results:
- Kcne3 deletion led to elevated serum aldosterone and adrenal lymphocyte infiltration in mice.
- Aldosterone-dependent ventricular repolarization delay (QTc prolongation) and increased susceptibility to post-ischemia arrhythmias were observed.
- A novel mechanism involving secondary hyperaldosteronism and adrenal autoimmunity was identified.
Conclusions:
- KCNE3 deletion causes arrhythmias through a novel pathway of secondary hyperaldosteronism and adrenal autoimmunity.
- Extracardiac pathogenesis, particularly adrenal dysfunction, is crucial in understanding inherited cardiac channelopathies.
