title: 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.
abstract: 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%).
  
  
  CONCLUSIONS
  Combined assessment of clinical and mutation-specific data can be used for improved risk stratification for life-threatening cardiac events in LQT2.
authors: Cardiology Division, University of Rochester Medical Center, Rochester, New York 14642, USA.
authors: Dimitry
authors: D
authors: Migdalovich
authors: Arthur J
authors: AJ
authors: Moss
authors: Coeli M
authors: CM
authors: Lopes
authors: Jason
authors: J
authors: Costa
authors: Gregory
authors: G
authors: Ouellet
authors: Alon
authors: A
authors: Barsheshet
authors: Scott
authors: S
authors: McNitt
authors: Slava
authors: S
authors: Polonsky
authors: Jennifer L
authors: JL
authors: Robinson
authors: Wojciech
authors: W
authors: Zareba
authors: Michael J
authors: MJ
authors: Ackerman
authors: Jesaia
authors: J
authors: Benhorin
authors: Elizabeth S
authors: ES
authors: Kaufman
authors: Pyotr G
authors: PG
authors: Platonov
authors: Wataru
authors: W
authors: Shimizu
authors: Jeffrey A
authors: JA
authors: Towbin
authors: G Michael
authors: GM
authors: Vincent
authors: Arthur A M
authors: AA
authors: Wilde
authors: Ilan
authors: I
authors: Goldenberg
mesh_terms: D000293:Adolescent; D000328:Adult; D016009:Chi-Square Distribution; D002648:Child; D002675:Child, Preschool; D016757:Death, Sudden, Cardiac; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics*; D005260:Female; D006323:Heart Arrest / Q000235:genetics / Q000401:mortality; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008133:Long QT Syndrome / Q000235:genetics* / Q000401:mortality; D008297:Male; D009154:Mutation; D011336:Probability; D016016:Proportional Hazards Models; D012042:Registries; D018570:Risk Assessment; D012737:Sex Factors; D018709:Statistics, Nonparametric; D016019:Survival Analysis
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human