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<jats:sec> <jats:title>Background—</jats:title> <jats:p> 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 <jats:sup>+</jats:sup> channel β subunit, are expressed in multiple tissues, suggesting potential multiplex SCD substrates. </jats:p> </jats:sec> <jats:sec> <jats:title>Methods and Results—</jats:title> <jats:p> Using whole-transcript transcriptomics, we uncovered cardiac angiotensinogen upregulation and remodeling of cardiac angiotensinogen interaction networks in P21 <jats:italic>Kcne2</jats:italic> <jats:sup>–/–</jats:sup> mouse pups and adrenal remodeling consistent with metabolic syndrome in adult <jats:italic>Kcne2</jats:italic> <jats:sup>–/–</jats:sup> mice. This led to the discovery that <jats:italic>Kcne2</jats:italic> disruption causes multiple acknowledged SCD substrates of extracardiac origin: diabetes mellitus, hypercholesterolemia, hyperkalemia, anemia, and elevated angiotensin II. <jats:italic>Kcne2</jats:italic> 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. </jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions—</jats:title> <jats:p>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.</jats:p> </jats:sec>
- 出版日期2014-2
