Combined assessment of sex- and mutation-specific information for risk stratification in type 1 long QT syndrome

Jason Costa, Coeli M. Lopes, Alon Barsheshet, Arthur J. Moss, Dmitriy Migdalovich, Gregory Ouellet, 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

Research output: Contribution to journalArticlepeer-review

40 Scopus citations


Background: Men and women with type 1 long QT syndrome (LQT1) exhibit time-dependent differences in the risk for cardiac events. Objective: We hypothesized that sex-specific risk for LQT1 is related to the location and function of the disease-causing mutation in the KCNQ1 gene. Methods: The risk for life-threatening cardiac events (comprising aborted cardiac arrest [ACA] or sudden cardiac death [SCD]) from birth through age 40 years was assessed among 1051 individuals with LQT1 (450 men and 601 women) by the location and function of the LQT1-causing mutation (prespecified as mutations in the intracellular domains linking the membrane-spanning segments [ie, S2-S3 and S4-S5 cytoplasmic loops] involved in adrenergic channel regulation vs other mutations). Results: Multivariate analysis showed that during childhood (age group: 0-13 years) men had >2-fold (P <.003) increased risk for ACA/SCD than did women, whereas after the onset of adolescence the risk for ACA/SCD was similar between men and women (hazard ratio = 0.89 [P =.64]). The presence of cytoplasmic-loop mutations was associated with a 2.7-fold (P <.001) increased risk for ACA/SCD among women, but it did not affect the risk among men (hazard ratio 1.37; P =.26). Time-dependent syncope was associated with a more pronounced risk-increase among men than among women (hazard ratio 4.73 [P <.001] and 2.43 [P =.02], respectively), whereas a prolonged corrected QT interval (<500 ms) was associated with a higher risk among women than among men. Conclusion: Our findings suggest that the combined assessment of clinical and mutation location/functional data can be used to identify sex-specific risk factors for life-threatening events for patients with LQT1.

Original languageEnglish (US)
Pages (from-to)892-898
Number of pages7
JournalHeart rhythm
Issue number6
StatePublished - Jun 2012


  • Cytoplasmic-loop mutations
  • Long QT syndrome
  • Sex
  • Sudden cardiac death

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)


Dive into the research topics of 'Combined assessment of sex- and mutation-specific information for risk stratification in type 1 long QT syndrome'. Together they form a unique fingerprint.

Cite this