Trigger-specific risk factors and response to therapy in long QT syndrome type 2

Background: Cardiac events in patients with long QT syndrome type 2 (LQT2) are predominately associated with sudden arousal. However, exercise-induced events also occur in this population.

Objective: The purpose of this study was to test the hypothesis that risk factors show a trigger-specific association with cardiac events in LQT2 patients.

Methods: The study population consisted of 634 genetically confirmed LQT2 patients from the U.S. portion of the International LQTS Registry. Multivariate Cox proportional hazards regression analysis was used to determine the independent contribution of clinical and genetic risk factors to the first occurrence of trigger-specific cardiac events, categorized as arousal, exercise-induced, and nonarousal/nonexercise, from birth through age 40 years.

Results: Study patients experienced 204 cardiac events during follow-up, of which 44% were associated with arousal triggers, 13% with exercise activity, and 43% with nonexercise/nonarousal triggers. Risk factors for arousal-triggered cardiac events included gender (female:male > 13 years: hazard ratio [HR] 9.10, P < .001) and the presence of pore-loop mutations (HR 2.19, P = .009). In contrast, non-pore-loop transmembrane mutations were the predominant risk factor for exercise-triggered events (HR 6.84, P < .001), whereas gender was not a significant risk factor for this endpoint. Nonexercise/nonarousal events were associated with heterogeneous causes. Risk factors for this endpoint included gender, mutation location and type, and prolonged QTc (≥ 500 m) Beta-blocker therapy was associated with a pronounced reduction in the risk for exercise-triggered events (HR 0.29, P < .01) but had a nonsignificant effect on the risk for arousal and nonexercise/nonarousal events.

Conclusion: The study findings suggest that management of patients with the LQT2 genotype should use a trigger-specific approach to risk assessment and medical therapy.