Overexpression of KCNN3 Results in Sudden Cardiac Death.

Cardiovascular Research

PubMedID: 24296650

Mahida S, Mills RW, Tucker NR, Simonson B, Macri V, Lemoine MD, Das S, Milan DJ, Ellinor PT. Overexpression of KCNN3 Results in Sudden Cardiac Death. Cardiovasc Res. 2014;101(2):326-34.
BackgroundA 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 to wild type (WT) controls. We observed a high incidence of sudden death amongst 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 to WT controls (SK3(T/T) vs. WT; 0.45±0.04 vs. 0.60±0.09 mm/ms, p=0.001). Programmed stimulation in one-month-old SK3(T/T) mice demonstrated inducible atrial arrhythmias (50% of SK3(T/T) vs. 0% of WT mice), as well as 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).

Overexpression of the SK3 channel causes an increased risk of sudden death associated with bradyarrhythmias and heart block, possibly due to atrioventricular nodal dysfunction.