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Atrium-specific Kir3.x determines inducibility, dynamics, and termination of fibrillation by regulating restitution-driven alternans

(2013) CIRCULATION. 128(25). p.2732-2744
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Abstract
Background—Atrial fibrillation is the most common cardiac arrhythmia. Ventricular proarrhythmia hinders pharmacological atrial fibrillation treatment. Modulation of atrium-specific Kir3.x channels, which generate a constitutively active current (IK,ACh-c) after atrial remodeling, might circumvent this problem. However, it is unknown whether and how IK,ACh-c contributes to atrial fibrillation induction, dynamics, and termination. Therefore, we investigated the effects of IK,ACh-c blockade and Kir3.x downregulation on atrial fibrillation. Methods and Results—Neonatal rat atrial cardiomyocyte cultures and intact atria were burst paced to induce reentry. To study the effects of Kir3.x on action potential characteristics and propagation patterns, cultures were treated with tertiapin or transduced with lentiviral vectors encoding Kcnj3- or Kcnj5-specific shRNAs. Kir3.1 and Kir3.4 were expressed in atrial but not in ventricular cardiomyocyte cultures. Tertiapin prolonged action potential duration (APD; 54.7±24.0 to 128.8±16.9 milliseconds; P<0.0001) in atrial cultures during reentry, indicating the presence of IK,ACh-c. Furthermore, tertiapin decreased rotor frequency (14.4±7.4 to 6.6±2.0 Hz; P<0.05) and complexity (6.6±7.7 to 0.6±0.8 phase singularities; P<0.0001). Knockdown of Kcnj3 or Kcnj5 gave similar results. Blockade of IK,ACh-c prevented/terminated reentry by prolonging APD and changing APD and conduction velocity restitution slopes, thereby altering the probability of APD alternans and rotor destabilization. Whole-heart mapping experiments confirmed key findings (eg, >50% reduction in atrial fibrillation inducibility after IK,ACh-c blockade). Conclusions—Atrium-specific Kir3.x controls the induction, dynamics, and termination of fibrillation by modulating APD and APD/conduction velocity restitution slopes in atrial tissue with IK,ACh-c. This study provides new molecular and mechanistic insights into atrial tachyarrhythmias and identifies Kir3.x as a promising atrium-specific target for antiarrhythmic strategies.
Keywords
G protein-coupled inwardly rectifying potassium channels, cardiomyocyte, arrhythmia, atrial fibrillation, action potentials, RNA interference, voltage-sensitive dye imaging, K+-CHANNEL PROTEINS, FOLLOW-UP, REPOLARIZATION ALTERNANS, CATHETER ABLATION, ACTION-POTENTIALS, POTASSIUM CURRENT, I-KACH, MECHANISMS, MORTALITY, ARRHYTHMIAS

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Chicago
Bingen, Brian O, Zeinab Neshati, Saïd FA Askar, Ivan Kazbanov, Dirk L Ypey, Alexander Panfilov, Martin J Schalij, Antoine AF de Vries, and Daniël A Pijnappels. 2013. “Atrium-specific Kir3.x Determines Inducibility, Dynamics, and Termination of Fibrillation by Regulating Restitution-driven Alternans.” Circulation 128 (25): 2732–2744.
APA
Bingen, B. O., Neshati, Z., Askar, S. F., Kazbanov, I., Ypey, D. L., Panfilov, A., Schalij, M. J., et al. (2013). Atrium-specific Kir3.x determines inducibility, dynamics, and termination of fibrillation by regulating restitution-driven alternans. CIRCULATION, 128(25), 2732–2744.
Vancouver
1.
Bingen BO, Neshati Z, Askar SF, Kazbanov I, Ypey DL, Panfilov A, et al. Atrium-specific Kir3.x determines inducibility, dynamics, and termination of fibrillation by regulating restitution-driven alternans. CIRCULATION. 2013;128(25):2732–44.
MLA
Bingen, Brian O, Zeinab Neshati, Saïd FA Askar, et al. “Atrium-specific Kir3.x Determines Inducibility, Dynamics, and Termination of Fibrillation by Regulating Restitution-driven Alternans.” CIRCULATION 128.25 (2013): 2732–2744. Print.
@article{4356971,
  abstract     = {Background—Atrial fibrillation is the most common cardiac arrhythmia. Ventricular proarrhythmia hinders pharmacological atrial fibrillation treatment. Modulation of atrium-specific Kir3.x channels, which generate a constitutively active current (IK,ACh-c) after atrial remodeling, might circumvent this problem. However, it is unknown whether and how IK,ACh-c contributes to atrial fibrillation induction, dynamics, and termination. Therefore, we investigated the effects of IK,ACh-c blockade and Kir3.x downregulation on atrial fibrillation.
Methods and Results—Neonatal rat atrial cardiomyocyte cultures and intact atria were burst paced to induce reentry. To study the effects of Kir3.x on action potential characteristics and propagation patterns, cultures were treated with tertiapin or transduced with lentiviral vectors encoding Kcnj3- or Kcnj5-specific shRNAs. Kir3.1 and Kir3.4 were expressed in atrial but not in ventricular cardiomyocyte cultures. Tertiapin prolonged action potential duration (APD; 54.7±24.0 to 128.8±16.9 milliseconds; P<0.0001) in atrial cultures during reentry, indicating the presence of IK,ACh-c. Furthermore, tertiapin decreased rotor frequency (14.4±7.4 to 6.6±2.0 Hz; P<0.05) and complexity (6.6±7.7 to 0.6±0.8 phase singularities; P<0.0001). Knockdown of Kcnj3 or Kcnj5 gave similar results. Blockade of IK,ACh-c prevented/terminated reentry by prolonging APD and changing APD and conduction velocity restitution slopes, thereby altering the probability of APD alternans and rotor destabilization. Whole-heart mapping experiments confirmed key findings (eg, >50% reduction in atrial fibrillation inducibility after IK,ACh-c blockade).
Conclusions—Atrium-specific Kir3.x controls the induction, dynamics, and termination of fibrillation by modulating APD and APD/conduction velocity restitution slopes in atrial tissue with IK,ACh-c. This study provides new molecular and mechanistic insights into atrial tachyarrhythmias and identifies Kir3.x as a promising atrium-specific target for antiarrhythmic strategies.},
  author       = {Bingen, Brian O and Neshati, Zeinab and Askar, Saïd FA and Kazbanov, Ivan and Ypey, Dirk L and Panfilov, Alexander and Schalij, Martin J and de Vries, Antoine AF and Pijnappels, Daniël A},
  issn         = {0009-7322},
  journal      = {CIRCULATION},
  keywords     = {G protein-coupled inwardly rectifying potassium channels,cardiomyocyte,arrhythmia,atrial fibrillation,action potentials,RNA interference,voltage-sensitive dye imaging,K+-CHANNEL PROTEINS,FOLLOW-UP,REPOLARIZATION ALTERNANS,CATHETER ABLATION,ACTION-POTENTIALS,POTASSIUM CURRENT,I-KACH,MECHANISMS,MORTALITY,ARRHYTHMIAS},
  language     = {eng},
  number       = {25},
  pages        = {2732--2744},
  title        = {Atrium-specific Kir3.x determines inducibility, dynamics, and termination of fibrillation by regulating restitution-driven alternans},
  url          = {http://dx.doi.org/10.1161/CIRCULATIONAHA.113.005019},
  volume       = {128},
  year         = {2013},
}

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