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

Dimitry Migdalovich, Arthur J. Moss, Coeli M. Lopes, Jason Costa, Gregory Ouellet, Alon Barsheshet, Scott McNitt, Slava Polonsky, Jennifer L. Robinson, Wojciech Zareba, Michael J. Ackerman, Jesaia Benhorin, Elizabeth S. Kaufman, Pyotr G. Platonov, Wataru Shimizu, Jeffrey A. Towbin, G. Michael Vincent, Arthur A. M. Wilde, Ilan Goldenberg

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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. This study sought to risk-stratify LQT2 patients for life-threatening cardiac events based on clinical and genetic information. 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). 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%). Combined assessment of clinical and mutation-specific data can be used for improved risk stratification for life-threatening cardiac events in LQT2
Original languageEnglish
Pages (from-to)1537-1543
JournalHeart rhythm
Issue number10
Publication statusPublished - 2011

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