Mutation and gender-specific risk in type 2 long QT syndrome: Implications for risk stratification for life-threatening cardiac events in patients with long QT syndrome

Background

Men and women with type 2 long QT syndrome (LQT2) exhibit time-dependent differences in the risk for cardiac events. We hypothesized that data regarding the location of the disease-causing mutation in the KCNH2 channel may affect gender-specific risk in LQT2.

Objective

This study sought to risk-stratify LQT2 patients for life-threatening cardiac events based on clinical and genetic information.

Methods

The risk for life-threatening cardiac events from birth through age 40 years (comprising aborted cardiac arrest [ACA] or sudden cardiac death [SCD]) was assessed among 1,166 LQT2 male (n = 490) and female (n = 676) patients by the location of the LQTS-causing mutation in the KCNH2 channel (prespecified in the primary analysis as pore-loop vs. non–pore-loop).

Results

During follow-up, the cumulative probability of life-threatening cardiac events years was significantly higher among LQT2 women (26%) as compared with men (14%; P <.001). Multivariate analysis showed that the risk for life-threatening cardiac events was not significantly different between women with and without pore-loop mutations (hazard ratio 1.20; P =.33). In contrast, men with pore-loop mutations displayed a significant >2-fold higher risk of a first ACA or SCD as compared with those with non–pore-loop mutations (hazard ratio 2.18; P = .01). Consistently, women experienced a high rate of life-threatening events regardless of mutation location (pore-loop: 35%, non–pore-loop: 23%), whereas in men the rate of ACA or SCD was high among those with pore-loop mutations (28%) and relatively low among those with non–pore-loop mutations (8%).

Conclusion

Combined assessment of clinical and mutation-specific data can be used for improved risk stratification for life-threatening cardiac events in LQT2.

Keywords: Long QT syndrome, Pore-loop mutations, Sudden cardiac death, Gender

Abbreviations: ACA, aborted cardiac arrest, ECG, electrocardiogram, ICD, implantable cardioverter-defibrillator, LQTS, long QT syndrome, LQT2, long QT syndrome type 2, QTc, corrected QT, SCD, sudden cardiac death