Trigger-specific ion-channel mechanisms, risk factors, and response to therapy in type 1 long QT syndrome

• Published in: Heart rhythm Vol. 9; no. 1; pp. 49 - 56
• Main Authors: Goldenberg, Ilan, MD, Thottathil, Princy, MD, Lopes, Coeli M., PhD, Moss, Arthur J., MD, McNitt, Scott, MS, O-Uchi, Jin, MD, PhD, Robinson, Jennifer L., MS, Zareba, Wojciech, MD, PhD, Ackerman, Michael J., MD, Kaufman, Elizabeth S., MD, Towbin, Jeffrey A., MD, Vincent, Michael, MD, Barsheshet, Alon, MD
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 2012
• Subjects: Adrenergic beta-Antagonists - therapeutic use; Cardiovascular; Death, Sudden, Cardiac - etiology; Electrocardiography; Exercise - physiology; Female; Humans; Ion Channels - genetics; Long QT Syndrome - complications; Long QT Syndrome - drug therapy; Long QT Syndrome - physiopathology; Long-QT syndrome; Male; Multivariate Analysis; Mutation; Precipitating Factors; Risk Factors; Sleep - physiology; Sudden cardiac death; Triggers; LQT2; LQT1; QTc; corrected QT interval; long-QT syndrome type 1; long-QT syndrome type 2; transmembrane; LQTS; aborted cardiac arrest; ECG; Long-QT syndrome; Triggers; Sudden cardiac death; electrocardiogram; C-loops; SCD; TM; cytoplasmic loops; ACA
• ISSN: 1547-5271; 1556-3871
• DOI: 10.1016/j.hrthm.2011.08.020

Background Arrhythmic events in long-QT syndrome type 1 (LQT1) may be associated with exercise, acute arousal, or rest/sleep. Objectives We aimed to identify trigger-specific risk factors for cardiac events in patients with LQT1. Methods The study population comprised 721 genetically confirmed patients with LQT1 from the US portion of the International LQTS Registry. Multivariate analysis was used to assess the independent contribution of prespecified clinical and mutation-specific factors to the development of a first reported triggered event, associated with exercise, arousal, or sleep/rest. Results Cardiac events occurred in 221 study patients, of whom 121 (55%) were associated with exercise, 30 (14%) with arousal, 47 (21%) with sleep/rest, and 23 (10%) with other triggers. Multivariate analysis showed that males <13 years had a 2.8-fold ( P < .001) increase in the risk for exercise-triggered events whereas females ≥13 years showed a 3.5-fold ( P = .002) increase in the risk for sleep/rest nonarousal events. Cytoplasmic-loop mutations within the transmembrane region, involved in adrenergic channel regulation, were associated with the increased risk for both exercise- and arousal-triggered events (hazard ratio = 6.19 [ P < .001] and 4.99 [ P < .001], respectively) but were not associated with events during sleep/rest (hazard ratio = 0.72; P = .46). Beta-blocker therapy was associated with a pronounced 78% ( P < .001) reduction in the risk for exercise-triggered events but did not have a significant effect on events associated with arousal or sleep/rest. Conclusions In patients with LQT1, cardiac events triggered by exercise, arousal, or rest/sleep are associated with distinctive risk factors and response to medical therapy. These findings can be used for improved recommendations for lifestyle modifications and therapeutic management in this population.