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.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Anemia / etiology
  • Angiotensin II / metabolism
  • Angiotensinogen / genetics
  • Angiotensinogen / metabolism
  • Animals
  • Arrhythmias, Cardiac / genetics*
  • Arrhythmias, Cardiac / pathology
  • Death, Sudden, Cardiac / etiology*
  • Diabetes Mellitus / etiology
  • Dyslipidemias / etiology
  • Gene Regulatory Networks
  • Genotype
  • Heterozygote
  • Hyperkalemia / etiology
  • Ischemia / etiology
  • Long QT Syndrome / genetics*
  • Long QT Syndrome / pathology
  • Mice
  • Mice, Knockout
  • Potassium Channels, Voltage-Gated / deficiency
  • Potassium Channels, Voltage-Gated / genetics*
  • Potassium Channels, Voltage-Gated / metabolism


  • Kcne2 protein, mouse
  • Potassium Channels, Voltage-Gated
  • Angiotensinogen
  • Angiotensin II