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

Arrhythmic events in long-QT syndrome type 1 (LQT1) may be associated with exercise, acute arousal, or rest/sleep. We aimed to identify trigger-specific risk factors for cardiac events in patients with LQT1. 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. 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. 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.