Overexpression of KCNN3 results in sudden cardiac death
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Overexpression of KCNN3 results in sudden cardiac death. / Mahida, Saagar; Mills, Robert W; Tucker, Nathan R; Simonson, Bridget; Macri, Vincenzo; Lemoine, Marc D; Das, Saumya; Milan, David J; Ellinor, Patrick T.
in: CARDIOVASC RES, Jahrgang 101, Nr. 2, 01.02.2014, S. 326-334.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Overexpression of KCNN3 results in sudden cardiac death
AU - Mahida, Saagar
AU - Mills, Robert W
AU - Tucker, Nathan R
AU - Simonson, Bridget
AU - Macri, Vincenzo
AU - Lemoine, Marc D
AU - Das, Saumya
AU - Milan, David J
AU - Ellinor, Patrick T
PY - 2014/2/1
Y1 - 2014/2/1
N2 - 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.
AB - 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.
KW - Action Potentials
KW - Animals
KW - Atrioventricular Node/abnormalities
KW - Bradycardia/genetics
KW - Cardiac Pacing, Artificial
KW - Connexin 43/metabolism
KW - Death, Sudden, Cardiac/etiology
KW - Electrocardiography, Ambulatory
KW - Genetic Predisposition to Disease
KW - Heart Block/genetics
KW - Heterozygote
KW - Homozygote
KW - Mice
KW - Mice, Transgenic
KW - Phenotype
KW - Small-Conductance Calcium-Activated Potassium Channels/genetics
KW - Time Factors
KW - Up-Regulation
KW - Voltage-Sensitive Dye Imaging
U2 - 10.1093/cvr/cvt269
DO - 10.1093/cvr/cvt269
M3 - SCORING: Journal article
C2 - 24296650
VL - 101
SP - 326
EP - 334
JO - CARDIOVASC RES
JF - CARDIOVASC RES
SN - 0008-6363
IS - 2
ER -