Kcne2 deletion creates a multisystem syndrome predisposing to sudden cardiac death
- Author(s): Hu, Z
- Kant, R
- Anand, M
- King, EC
- Krogh-Madsen, T
- Christini, DJ
- Abbott, GW
- et al.
Published Web Locationhttps://doi.org/10.1161/CIRCGENETICS.113.000315
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 ß 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. © 2014 American Heart Association, Inc.
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