Abstract 285: Overexpression of SK3 in a Murine Model Results in Sudden Cardiac Death
Background: Recently, the gene responsible for encoding SK3, KCNN3, was implicated in a genome-wide association study as a susceptibility locus for atrial fibrillation. SK3 is one of a family of three small conductance, voltage-independent, calcium-activated potassium channels which is abundantly expressed in cardiac tissues. Therefore, we hypothesized that transcriptional misregulation of the KCNN3 gene could result in arrhythmogenesis.
Methods: We characterized a mouse line which had constitutive ubiquitous overexpression of Kcnn3 using ambulatory cardiac rhythm monitoring, optical mapping and in vivo electrophysiology studies. Both homozygote (SK3T/T) and heterozygote (SK3T/+) animals were compared to their wild-type (SK3+/+) littermates for assessment of cardiac phenotypes.
Results: SK3T/T mice displayed increased expression of SK3, as assessed by qRT-PCR, in all four chambers of the heart, although highest increase of expression was observed in the ventricles. Examinations of SK3T/T mice revealed no gross morphological changes in the myocardium, no observable cardiac fibrosis, and normal echocardiograms when compared to SK3+/+ mice. However, pups from SK3T/+ crosses did not produce expected Mendelian ratios (SK3+/+ = 17%), and 7 out of 19 SK3+/+ mice died suddenly by 3 months of age, whereas all of the SK3T/+ or SK3+/+ survived. To address potential mechanisms, we performed ambulatory monitoring on mice beginning at approximately one month of age. Of the 6 SK3+/+ mice, 4 died suddenly, whereas neither of the wild-type controls expired. The cardiac rhythm recorded at the time of death in three of the four mice was heart block followed by severe bradycardia. Additionally, during the period of ambulatory monitoring, SK3T/T mice had a lower mean heart rate compared to the SK3+/+ control mice, and SK3T/T mice also displayed frequent episodes of atrioventricular dissociation, both at rest and during periods of activity. SK3T/T mice also displayed more pronounced variability of the heart rate and the PR interval. Optical mapping revealed slower ventricular conduction velocity.
Conclusion: These data suggest a mechanism whereby overexpression of SK3 leads to sudden death due to bradyarrhythmias and heart block.
- © 2013 by American Heart Association, Inc.