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Kcne2 Deletion Creates a Multisystem Syndrome Predisposing to Sudden Cardiac Death
Journal Title
Circulation: Cardiovascular Genetics
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Publication Date
2014-02
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Publication Volume
7
Publication Issue
1
Publication Begin
33
Publication End
42
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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.
Citation
Hu Z, Kant R, Anand M, King EC, Krogh-Madsen T, Christini DJ, Abbott GW. Kcne2 deletion creates a multisystem syndrome predisposing to sudden cardiac death. Circ Cardiovasc Genet. 2014 Feb;7(1):33-42. doi: 10.1161/CIRCGENETICS.113.000315. Epub 2014 Jan 8. PMID: 24403551; PMCID: PMC4917016.