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

Costa, Jason; Lopes, Coeli M.; Barsheshet, Alon; Moss, Arthur J.; Migdalovich, Dmitriy; Ouellet, Gregory; McNitt, Scott; Polonsky, Slava; Robinson, Jennifer L. and Zareba, Wojciech, et al. (2012) In Heart Rhythm 9(6). p.892-898
Abstract
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... (More)
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. (Less)
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Contribution to journal
publication status
published
subject
keywords
Cytoplasmic-loop mutations, Sex, Long QT syndrome, Sudden cardiac death
in
Heart Rhythm
volume
9
issue
6
pages
892 - 898
publisher
Elsevier
external identifiers
  • wos:000304242900012
  • scopus:84861336766
ISSN
1547-5271
DOI
10.1016/j.hrthm.2012.01.020
language
English
LU publication?
yes
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3dea97a6-45ee-4fed-9a88-89532ea67fff (old id 2799692)
date added to LUP
2012-07-03 10:25:07
date last changed
2017-05-21 03:12:39
@article{3dea97a6-45ee-4fed-9a88-89532ea67fff,
  abstract     = {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 &gt;2-fold (P &lt; .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 &lt; .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 &lt; .001] and 2.43 [P = .02], respectively), whereas a prolonged corrected QT interval (&gt;= 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.},
  author       = {Costa, Jason and Lopes, Coeli M. and Barsheshet, Alon and Moss, Arthur J. and Migdalovich, Dmitriy and Ouellet, Gregory and McNitt, Scott and Polonsky, Slava and Robinson, Jennifer L. and Zareba, Wojciech and Ackerman, Michael J. and Benhorin, Jesaia and Kaufman, Elizabeth S. and Platonov, Pyotr and Shimizu, Wataru and Towbin, Jeffrey A. and Vincent, G. Michael and Wilde, Arthur A. M. and Goldenberg, Ilan},
  issn         = {1547-5271},
  keyword      = {Cytoplasmic-loop mutations,Sex,Long QT syndrome,Sudden cardiac death},
  language     = {eng},
  number       = {6},
  pages        = {892--898},
  publisher    = {Elsevier},
  series       = {Heart Rhythm},
  title        = {Combined assessment of sex- and mutation-specific information for risk stratification in type 1 long QT syndrome},
  url          = {http://dx.doi.org/10.1016/j.hrthm.2012.01.020},
  volume       = {9},
  year         = {2012},
}