Zhaoyang Zhang1, Peng-Sheng Chen2, James N Weiss3, Zhilin Qu3,4. 1. Department of Physics, School of Physical Science and Technology, Ningbo University, Zhejiang, China (Z.Z.). 2. Department of Cardiology, Smidt Heart Institute, Cedars Sinai Medical Center, Los Angeles, CA (P.-S.C.). 3. Department of Medicine (J.N.W., Z.Q.), David Geffen School of Medicine, University of California, Los Angeles. 4. Department of Computational Medicine (Z.Q.), David Geffen School of Medicine, University of California, Los Angeles.
Abstract
BACKGROUND: Three types of characteristic ST-segment elevation are associated with Brugada syndrome but only type 1 is diagnostic. Why only type 1 ECG is diagnostic remains unanswered. METHODS: Computer simulations were performed in single cells, 1-dimensional cables, and 2-dimensional tissues to investigate the effects of the peak and late components of the transient outward potassium current (Ito), sodium current, and L-type calcium current (ICa,L) as well as other potassium currents on the genesis of ECG morphologies and phase 2 reentry (P2R). RESULTS: Although a sufficiently large peak Ito was required to result in the type 1 ECG pattern and P2R, increasing the late component of Ito converted type 1 ECG to type 2 ECG and suppressed P2R. Increasing the peak Ito promoted spiral wave breakup, potentiating the transition from tachycardia to fibrillation, but increasing the late Ito prevented spiral wave breakup by flattening the action potential duration restitution and preventing P2R. A sufficiently large ICa,L conductance was needed for P2R to occur, but once above the critical conductance, blocking ICa,L promoted P2R. However, selectively blocking the window and late components of ICa,L suppressed P2R, countering the effect of the late Ito. Blocking either the peak or late components of sodium current promoted P2R, with the late sodium current blockade having the larger effect. As expected, increasing other potassium currents potentiated P2R, with ATP-sensitive potassium current exhibiting a larger effect than rapid and slow component of the delayed rectifier potassium current. CONCLUSIONS: The peak Ito promotes type 1 ECG and P2R, whereas the late Ito converts type 1 ECG to type 2 ECG and suppresses P2R. Blocking the peak ICa,L and either the peak or the late sodium current promotes P2R, whereas blocking the window and late ICa,L suppresses P2R. These results provide important insights into the mechanisms of arrhythmogenesis and potential therapeutic targets for treatment of Brugada syndrome. Graphic Abstract: A graphic abstract is available for this article.
BACKGROUND: Three types of characteristic ST-segment elevation are associated with Brugada syndrome but only type 1 is diagnostic. Why only type 1 ECG is diagnostic remains unanswered. METHODS: Computer simulations were performed in single cells, 1-dimensional cables, and 2-dimensional tissues to investigate the effects of the peak and late components of the transient outward potassium current (Ito), sodium current, and L-type calcium current (ICa,L) as well as other potassium currents on the genesis of ECG morphologies and phase 2 reentry (P2R). RESULTS: Although a sufficiently large peak Ito was required to result in the type 1 ECG pattern and P2R, increasing the late component of Ito converted type 1 ECG to type 2 ECG and suppressed P2R. Increasing the peak Ito promoted spiral wave breakup, potentiating the transition from tachycardia to fibrillation, but increasing the late Ito prevented spiral wave breakup by flattening the action potential duration restitution and preventing P2R. A sufficiently large ICa,L conductance was needed for P2R to occur, but once above the critical conductance, blocking ICa,L promoted P2R. However, selectively blocking the window and late components of ICa,L suppressed P2R, countering the effect of the late Ito. Blocking either the peak or late components of sodium current promoted P2R, with the late sodium current blockade having the larger effect. As expected, increasing other potassium currents potentiated P2R, with ATP-sensitive potassium current exhibiting a larger effect than rapid and slow component of the delayed rectifier potassium current. CONCLUSIONS: The peak Ito promotes type 1 ECG and P2R, whereas the late Ito converts type 1 ECG to type 2 ECG and suppresses P2R. Blocking the peak ICa,L and either the peak or the late sodium current promotes P2R, whereas blocking the window and late ICa,L suppresses P2R. These results provide important insights into the mechanisms of arrhythmogenesis and potential therapeutic targets for treatment of Brugada syndrome. Graphic Abstract: A graphic abstract is available for this article.
Authors: R Dumaine; J A Towbin; P Brugada; M Vatta; D V Nesterenko; V V Nesterenko; J Brugada; R Brugada; C Antzelevitch Journal: Circ Res Date: 1999-10-29 Impact factor: 17.367
Authors: Silvia G Priori; Carina Blomström-Lundqvist; Andrea Mazzanti; Nico Blom; Martin Borggrefe; John Camm; Perry Mark Elliott; Donna Fitzsimons; Robert Hatala; Gerhard Hindricks; Paulus Kirchhof; Keld Kjeldsen; Karl-Heinz Kuck; Antonio Hernandez-Madrid; Nikolaos Nikolaou; Tone M Norekvål; Christian Spaulding; Dirk J Van Veldhuisen Journal: Eur Heart J Date: 2015-08-29 Impact factor: 29.983
Authors: Darwin Jeyaraj; Saptarsi M Haldar; Xiaoping Wan; Mark D McCauley; Jürgen A Ripperger; Kun Hu; Yuan Lu; Betty L Eapen; Nikunj Sharma; Eckhard Ficker; Michael J Cutler; James Gulick; Atsushi Sanbe; Jeffrey Robbins; Sophie Demolombe; Roman V Kondratov; Steven A Shea; Urs Albrecht; Xander H T Wehrens; David S Rosenbaum; Mukesh K Jain Journal: Nature Date: 2012-02-22 Impact factor: 49.962