Jin O-Uchi1, J Jeremy Rice2, Martin H Ruwald3, Xiaorong Xu Parks1, Elsa Ronzier1, Arthur J Moss3, Wojciech Zareba3, Coeli M Lopes4. 1. Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, New York, USA. 2. Functional Genomics and Systems Biology Group, IBM T.J. Watson Research Center, New York, USA. 3. Cardiology Division, Department of Medicine, University of Rochester School of Medicine and Dentistry, New York, USA. 4. Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, New York, USA. Electronic address: coeli_lopes@urmc.rochester.edu.
Abstract
BACKGROUND: The most common inherited cardiac arrhythmia, LQT1, is due to IKs potassium channel mutations and is linked to high risk of adrenergic-triggered cardiac events. We recently showed that although exercise-triggered events are very well treated by ß-blockers for these patients, acute arousal-triggered event rate were not significantly reduced after beta-blocker treatment, suggesting that the mechanisms underlying arousal-triggered arrhythmias may be different from those during exercise. IKs is strongly regulated by β-adrenergic receptor (β-AR) signaling, but little is known about the role of α1-AR-mediated regulation. METHODS AND RESULTS: Here we show, using a combination of cellular electrophysiology and computational modeling, that IKs phosphorylation and α1-AR regulation via activation of calcium-dependent PKC isoforms (cPKC) may be a key mechanism to control channel voltage-dependent activation and consequently action potential duration (APD) in response to adrenergic-stimulus. We show that simulated mutation-specific combined adrenergic effects (β+α) on APD were strongly correlated to acute stress-triggered cardiac event rate for patients while β-AR effects alone were not. CONCLUSION: We were able to show that calcium-dependent PKC signaling is key to normal QT shortening during acute arousal and when impaired, correlates with increased rate of sudden arousal-triggered cardiac events. Our study suggests that the acute α1-AR-cPKC regulation of IKs is important for QT shortening in "fight-or-flight" response and is linked to decreased risk of sudden emotion/arousal-triggered cardiac events in LQT1 patients.
BACKGROUND: The most common inherited cardiac arrhythmia, LQT1, is due to IKs potassium channel mutations and is linked to high risk of adrenergic-triggered cardiac events. We recently showed that although exercise-triggered events are very well treated by ß-blockers for these patients, acute arousal-triggered event rate were not significantly reduced after beta-blocker treatment, suggesting that the mechanisms underlying arousal-triggered arrhythmias may be different from those during exercise. IKs is strongly regulated by β-adrenergic receptor (β-AR) signaling, but little is known about the role of α1-AR-mediated regulation. METHODS AND RESULTS: Here we show, using a combination of cellular electrophysiology and computational modeling, that IKs phosphorylation and α1-AR regulation via activation of calcium-dependent PKC isoforms (cPKC) may be a key mechanism to control channel voltage-dependent activation and consequently action potential duration (APD) in response to adrenergic-stimulus. We show that simulated mutation-specific combined adrenergic effects (β+α) on APD were strongly correlated to acute stress-triggered cardiac event rate for patients while β-AR effects alone were not. CONCLUSION: We were able to show that calcium-dependent PKC signaling is key to normal QT shortening during acute arousal and when impaired, correlates with increased rate of sudden arousal-triggered cardiac events. Our study suggests that the acute α1-AR-cPKC regulation of IKs is important for QT shortening in "fight-or-flight" response and is linked to decreased risk of sudden emotion/arousal-triggered cardiac events in LQT1patients.
Authors: Alon Barsheshet; Arthur J Moss; Scott McNitt; Slava Polonsky; Coeli M Lopes; Wojciech Zareba; Jennifer L Robinson; Michael J Ackerman; Jesaia Benhorin; Elizabeth S Kaufman; Jeffrey A Towbin; G Michael Vincent; Ming Qi; Ilan Goldenberg Journal: Circ Cardiovasc Genet Date: 2011-08-10
Authors: Ilan Goldenberg; Princy Thottathil; Coeli M Lopes; Arthur J Moss; Scott McNitt; Jin O-Uchi; Jennifer L Robinson; Wojciech Zareba; Michael J Ackerman; Elizabeth S Kaufman; Jeffrey A Towbin; Michael Vincent; Alon Barsheshet Journal: Heart Rhythm Date: 2011-08-24 Impact factor: 6.343
Authors: P J Schwartz; S G Priori; C Spazzolini; A J Moss; G M Vincent; C Napolitano; I Denjoy; P Guicheney; G Breithardt; M T Keating; J A Towbin; A H Beggs; P Brink; A A Wilde; L Toivonen; W Zareba; J L Robinson; K W Timothy; V Corfield; D Wattanasirichaigoon; C Corbett; W Haverkamp; E Schulze-Bahr; M H Lehmann; K Schwartz; P Coumel; R Bloise Journal: Circulation Date: 2001-01-02 Impact factor: 29.690
Authors: Alon Barsheshet; Ilan Goldenberg; Jin O-Uchi; Arthur J Moss; Christian Jons; Wataru Shimizu; Arthur A Wilde; Scott McNitt; Derick R Peterson; Wojciech Zareba; Jennifer L Robinson; Michael J Ackerman; Michael Cypress; Daniel A Gray; Nynke Hofman; Jorgen K Kanters; Elizabeth S Kaufman; Pyotr G Platonov; Ming Qi; Jeffrey A Towbin; G Michael Vincent; Coeli M Lopes Journal: Circulation Date: 2012-03-28 Impact factor: 29.690
Authors: Christian Jons; Jin O-Uchi; Arthur J Moss; Matthias Reumann; John J Rice; Ilan Goldenberg; Wojciech Zareba; Arthur A M Wilde; Wataru Shimizu; Jorgen K Kanters; Scott McNitt; Nynke Hofman; Jennifer L Robinson; Coeli M B Lopes Journal: Sci Transl Med Date: 2011-03-30 Impact factor: 17.956
Authors: Samuel Horr; Ilan Goldenberg; Arthur J Moss; Jin O-Uchi; Alon Barsheshet; Heather Connelly; Daniel A Gray; Wojciech Zareba; Coeli M B Lopes Journal: J Cardiovasc Electrophysiol Date: 2011-02