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.
Bibliographical noteFunding Information:
The authors thank Dr. Elena Fujiwara, Ms. Nobiru Suzuki, Ms. Mehreen Butt and Mr. Michael Cypress for their technical assistance. This work was partly supported by AHA grants ( 09POST2310079 and 14BGIA18830032 to J.O.-U.), Foreign Study Grant Award of Kanae Foundation (to J.O.-U.), Irisawa Memorial Promotion Award for Young Physiologists from the Physiological Society of Japan (to J.O.-U.) NIH R01HL123483 (A.J.M.) and NIH R01HL114792 (to C.M.B.L.).