Overexpression of KCNN3 results in sudden cardiac death
| Autor: | Saagar Mahida, Marc D. Lemoine, David J. Milan, Robert W. Mills, Bridget Simonson, Nathan R. Tucker, Patrick T. Ellinor, Vincenzo Macri, Saumya Das |
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| Rok vydání: | 2013 |
| Předmět: |
Bradycardia
Cardiac function curve medicine.medical_specialty Physiology Heart block Atrial fibrillation Biology medicine.disease Sudden death Atrioventricular node Potassium channel Sudden cardiac death medicine.anatomical_structure Endocrinology Physiology (medical) Internal medicine medicine Cardiology medicine.symptom Cardiology and Cardiovascular Medicine |
| Zdroj: | Cardiovascular Research. 101:326-334 |
| ISSN: | 1755-3245 0008-6363 |
| Popis: | 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 ( SK3T/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 SK3T/T mice (7 of 19 SK3T/T mice). Ambulatory monitoring demonstrated that sudden death was due to heart block and bradyarrhythmias. SK3T/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 SK3T/T mice have slower ventricular conduction compared with WT controls ( SK3T/T vs. WT; 0.45 ± 0.04 vs. 0.60 ± 0.09 mm/ms, P = 0.001). Programmed stimulation in 1-month-old SK3T/T mice demonstrated inducible atrial arrhythmias (50% of SK3T/T vs. 0% of WT mice) and also a shorter atrioventricular nodal refractory period ( SK3T/T vs. WT; 43 ± 6 vs. 52 ± 9 ms, P = 0.02). Three-month-old SK3T/T mice on the other hand displayed a trend towards a more prolonged atrioventricular nodal refractory period ( SK3T/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. |
| Databáze: | OpenAIRE |
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