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Circ Cardiovasc Genet. 2014 Feb;7(1):33-42. doi: 10.1161/CIRCGENETICS.113.000315. Epub 2014 Jan 8.

Kcne2 deletion creates a multisystem syndrome predisposing to sudden cardiac death.

Author information

1
Bioelectricity Laboratory, Departments of Pharmacology and Physiology and Biophysics, School of Medicine, University of California, Irvine.

Abstract

BACKGROUND:

Sudden cardiac death (SCD) is the leading global cause of mortality, exhibiting increased incidence in patients with diabetes mellitus. Ion channel gene perturbations provide a well-established ventricular arrhythmogenic substrate for SCD. However, most arrhythmia-susceptibility genes, including the KCNE2 K(+) channel β subunit, are expressed in multiple tissues, suggesting potential multiplex SCD substrates.

METHODS AND RESULTS:

Using whole-transcript transcriptomics, we uncovered cardiac angiotensinogen upregulation and remodeling of cardiac angiotensinogen interaction networks in P21 Kcne2(-/-) mouse pups and adrenal remodeling consistent with metabolic syndrome in adult Kcne2(-/-) mice. This led to the discovery that Kcne2 disruption causes multiple acknowledged SCD substrates of extracardiac origin: diabetes mellitus, hypercholesterolemia, hyperkalemia, anemia, and elevated angiotensin II. Kcne2 deletion was also a prerequisite for aging-dependent QT prolongation, ventricular fibrillation and SCD immediately after transient ischemia, and fasting-dependent hypoglycemia, myocardial ischemia, and AV block.

CONCLUSIONS:

Disruption of a single, widely expressed arrhythmia-susceptibility gene can generate a multisystem syndrome comprising manifold electric and systemic substrates and triggers of SCD. This paradigm is expected to apply to other arrhythmia-susceptibility genes, the majority of which encode ubiquitously expressed ion channel subunits or regulatory proteins.

KEYWORDS:

arrhythmias, cardiac; death; ion channels; ischemia; potassium; sudden, cardiac

Comment in

PMID:
24403551
PMCID:
PMC4917016
DOI:
10.1161/CIRCGENETICS.113.000315
[Indexed for MEDLINE]
Free PMC Article

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