Key result
Overexpression of the SK3 channel in mice resulted in a high incidence of sudden death (36.8% of homozygote mice) associated with bradyarrhythmias and heart block.
Why the study?
Does overexpression of the SK3 channel increase susceptibility to cardiac arrhythmias and sudden death in a mouse model?
Does overexpression of the SK3 channel increase susceptibility to cardiac arrhythmias and sudden death in a mouse model?
Overexpression of the SK3 channel in mice increases the risk of sudden death from bradyarrhythmias and heart block, highlighting its potential role in atrioventricular nodal dysfunction.
Overexpression of SK3 promotes arrhythmias in mice; leaves open whether KCNN3 variants affect human AF risk.
BACKGROUND: A recent genome-wide association study identified a susceptibility locus for atrial fibrillation at the KCNN3 gene. Since the KCNN3 gene encodes for a small conductance calcium-activated potassium channel, we hypothesized that overexpression of the SK3 channel increases susceptibility to cardiac arrhythmias. METHODS AND RESULTS: We characterized the cardiac electrophysiological phenotype of a mouse line with overexpression of the SK3 channel. We generated homozygote (SK3(T/T)) and heterozygote (SK3(+/T)) mice with overexpression of the channel and compared them with wild-type (WT) controls. We observed a high incidence of sudden death among SK3(T/T) mice (7 of 19 SK3(T/T) mice). Ambulatory monitoring demonstrated that sudden death was due to heart block and bradyarrhythmias. SK3(T/T) mice displayed normal body weight, temperature, and cardiac function on echocardiography; however, histological analysis demonstrated that these mice have abnormal atrioventricular node morphology. Optical mapping demonstrated that SK3(T/T) mice have slower ventricular conduction compared with WT controls (SK3(T/T) vs. WT; 0.45 ± 0.04 vs. 0.60 ± 0.09 mm/ms, P = 0.001). Programmed stimulation in 1-month-old SK3(T/T) mice demonstrated inducible atrial arrhythmias (50% of SK3(T/T) vs. 0% of WT mice) and also a shorter atrioventricular nodal refractory period (SK3(T/T) vs. WT; 43 ± 6 vs. 52 ± 9 ms, P = 0.02). Three-month-old SK3(T/T) mice on the other hand displayed a trend towards a more prolonged atrioventricular nodal refractory period (SK3(T/T) vs. WT; 61 ± 1 vs. 52 ± 6 ms, P = 0.06). CONCLUSION: Overexpression of the SK3 channel causes an increased risk of sudden death associated with bradyarrhythmias and heart block, possibly due to atrioventricular nodal dysfunction.
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Mahida et al. (2013) studied Cardiac arrhythmias and sudden cardiac death. Overexpression of the SK3 channel (KCNN3 gene) vs. Wild-type (WT) controls was evaluated on Sudden death. Overexpression of the SK3 channel in mice resulted in a high incidence of sudden death (36.8% of homozygote mice) associated with bradyarrhythmias and heart block.
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