BACKGROUND: -Risk stratification in patients with type 3 long QT syndrome (LQT3) by clinical and genetic characteristics and effectiveness of ß-blocker therapy have not been studied previously in a large LQT3 population.

METHODS: -The study population included 406 LQT3 patients with 51 different sodium-channel mutations; 391 patients were known to be event free during the first year of life and were the focus of our study. Clinical, electrocardiographic, and genetic parameters were acquired on patients from 7 participating LQT3 registries. Cox regression analysis was used to evaluate the independent contribution of clinical, genetic, and therapeutic factors to the first occurrence of time-dependent cardiac events (CE) from age 1 to 41 years.

RESULTS: -118 (30%) patients (41 males) experienced at least one CE (syncope, aborted cardiac arrest [ACA] or LQTS-related sudden death [SD]), and 20% suffered from LQT3-related ACA/SD. The risk of a first CE was directly related to the degree of QTc prolongation. Cox regression analysis revealed that time-dependent ß-blocker therapy was associated with an 83% reduction in CE's in females (p=0.015) but not in males (who had much fewer events), with a significant gender x ß-blocker interaction (p=0.04). Each 10ms increase in QTc duration up to 500ms was associated with a 19% increase in CE's. Prior syncope doubled the risk for life-threatening events (p<0.02).

CONCLUSIONS: -Prolonged QTc and syncope predispose patients with LQT3 to life-threatening CE's. ß-blocker therapy reduces this risk in females, but efficacy in males could not be conclusively determined due to low number of events.