title: Overexpression of KCNN3 results in sudden cardiac death.
abstract: 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.
  
  
  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).
  
  
  CONCLUSIONS
  Overexpression of the SK3 channel causes an increased risk of sudden death associated with bradyarrhythmias and heart block, possibly due to atrioventricular nodal dysfunction.
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA, USA.
authors.forename: Saagar
authors.initials: S
authors.lastname: Mahida
authors.forename: Robert W
authors.initials: RW
authors.lastname: Mills
authors.forename: Nathan R
authors.initials: NR
authors.lastname: Tucker
authors.forename: Bridget
authors.initials: B
authors.lastname: Simonson
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Macri
authors.forename: Marc D
authors.initials: MD
authors.lastname: Lemoine
authors.forename: Saumya
authors.initials: S
authors.lastname: Das
authors.forename: David J
authors.initials: DJ
authors.lastname: Milan
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Ellinor
mesh_terms: D000200:Action Potentials; D000818:Animals; D001283:Atrioventricular Node / Q000002:abnormalities / Q000378:metabolism* / Q000503:physiopathology; D001919:Bradycardia / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D002304:Cardiac Pacing, Artificial; D018031:Connexin 43 / Q000378:metabolism; D016757:Death, Sudden, Cardiac / Q000209:etiology*; D015716:Electrocardiography, Ambulatory; D020022:Genetic Predisposition to Disease; D006327:Heart Block / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D006579:Heterozygote; D006720:Homozygote; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D015854:Up-Regulation; D056969:Voltage-Sensitive Dye Imaging
chemical_list: D018031:Connexin 43; C543076:GJA1 protein, mouse; C496900:Kcnn3 protein, mouse; D051640:Small-Conductance Calcium-Activated Potassium Channels
keywords: Arrhythmias; Atrial fibrillation; Heart block; Ion channels; Potassium channel