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.


CONCLUSIONS
The study findings suggest that management of patients with the LQT2 genotype should use a trigger-specific approach to risk assessment and medical therapy.
Kim
James A
JA
Cardiology Division, Department of Medicine, University of Rochester Medical Center, Rochester, New York, USA.
Lopes
Coeli M
CM
Moss
Arthur J
AJ
McNitt
Scott
S
Barsheshet
Alon
A
Robinson
Jennifer L
JL
Zareba
Wojciech
W
Ackerman
Michael J
MJ
Kaufman
Elizabeth S
ES
Towbin
Jeffrey A
JA
Vincent
Michael
M
Goldenberg
Ilan
I
D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use; D001143:Arousal / Q000502:physiology; D016757:Death, Sudden, Cardiac / Q000209:etiology; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics; D015444:Exercise / Q000502:physiology; D005838:Genotype; D006323:Heart Arrest / Q000235:genetics; D006801:Humans; D007473:Ion Channels / Q000235:genetics; D008133:Long QT Syndrome / Q000151:congenital / Q000188:drug therapy / Q000453:epidemiology* / Q000235:genetics*; D009154:Mutation; D016016:Proportional Hazards Models; D018570:Risk Assessment; D012307:Risk Factors; D012737:Sex Factors; D013575:Syncope / Q000235:genetics
D000319:Adrenergic beta-Antagonists; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D007473:Ion Channels