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Risk Stratification of Type 2 Long-QT Syndrome Mutation Carriers with Normal QTc Interval : The Value of Sex, T-Wave Morphology, and Mutation Type

Platonov, Pyotr G. LU ; McNitt, Scott; Polonsky, Bronislava; Rosero, Spencer Z.; Kutyifa, Valentina; Huang, Allison; Moss, Arthur J. and Zareba, Wojciech (2018) In Circulation: Arrhythmia and Electrophysiology 11(7).
Abstract

Background: Long-QT (LQT) syndrome mutation carriers have higher risk of cardiac events than unaffected family members even in the absence of QTc prolongation. Changes in T-wave morphology may reflect penetrance of LQT syndrome mutations. We aimed to assess whether T-wave morphology may improve risk stratification of LQT2 mutation carriers with normal QTc interval. Methods: LQT2 mutation carriers with QTc <460 ms in men and <470 ms in women (n=154) were compared with unaffected family members (n=1007). Baseline ECGs recorded at age ≥18 years underwent blinded assessment. Flat, notched, or negative T waves in leads II or V5 were considered abnormal. Cox regression analysis was performed to assess the association between T-wave... (More)

Background: Long-QT (LQT) syndrome mutation carriers have higher risk of cardiac events than unaffected family members even in the absence of QTc prolongation. Changes in T-wave morphology may reflect penetrance of LQT syndrome mutations. We aimed to assess whether T-wave morphology may improve risk stratification of LQT2 mutation carriers with normal QTc interval. Methods: LQT2 mutation carriers with QTc <460 ms in men and <470 ms in women (n=154) were compared with unaffected family members (n=1007). Baseline ECGs recorded at age ≥18 years underwent blinded assessment. Flat, notched, or negative T waves in leads II or V5 were considered abnormal. Cox regression analysis was performed to assess the association between T-wave morphology, the presence of mutations in the pore region of KCNH2, and the risk of cardiac events defined as syncope, aborted cardiac arrest, defibrillator therapy, or sudden cardiac death. Sex-specific associations were estimated using interactions terms. Results: LQT2 female carriers with abnormal T-wave morphology had significantly higher risk of cardiac events compared with LQT2 female carriers with normal T waves (hazard ratio, 3.31; 95% confidence interval, 1.68-6.52; P=0.001), whereas this association was not significant in men. LQT2 men with pore location of mutations have significantly higher risk of cardiac events than those with nonpore mutations (hazard ratio, 6.01; 95% confidence interval, 1.50-24.08; P=0.011), whereas no such association was found in women. Conclusions: The risk of cardiac events in LQT2 carriers with normal QTc is associated with abnormal T-wave morphology in women and pore location of mutation in men. The findings further indicate sex-specific differences in phenotype and genotype relationship in LQT2 patients.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
genotype, long-QT syndrome, mutation, risk, sex
in
Circulation: Arrhythmia and Electrophysiology
volume
11
issue
7
publisher
Lippincott Williams & Wilkins
external identifiers
  • scopus:85060484367
ISSN
1941-3149
DOI
10.1161/CIRCEP.117.005918
language
English
LU publication?
yes
id
884b7405-db82-4574-b2d8-c0584c8a3753
date added to LUP
2019-02-08 12:32:19
date last changed
2019-08-14 04:32:12
@article{884b7405-db82-4574-b2d8-c0584c8a3753,
  abstract     = {<p>Background: Long-QT (LQT) syndrome mutation carriers have higher risk of cardiac events than unaffected family members even in the absence of QTc prolongation. Changes in T-wave morphology may reflect penetrance of LQT syndrome mutations. We aimed to assess whether T-wave morphology may improve risk stratification of LQT2 mutation carriers with normal QTc interval. Methods: LQT2 mutation carriers with QTc &lt;460 ms in men and &lt;470 ms in women (n=154) were compared with unaffected family members (n=1007). Baseline ECGs recorded at age ≥18 years underwent blinded assessment. Flat, notched, or negative T waves in leads II or V5 were considered abnormal. Cox regression analysis was performed to assess the association between T-wave morphology, the presence of mutations in the pore region of KCNH2, and the risk of cardiac events defined as syncope, aborted cardiac arrest, defibrillator therapy, or sudden cardiac death. Sex-specific associations were estimated using interactions terms. Results: LQT2 female carriers with abnormal T-wave morphology had significantly higher risk of cardiac events compared with LQT2 female carriers with normal T waves (hazard ratio, 3.31; 95% confidence interval, 1.68-6.52; P=0.001), whereas this association was not significant in men. LQT2 men with pore location of mutations have significantly higher risk of cardiac events than those with nonpore mutations (hazard ratio, 6.01; 95% confidence interval, 1.50-24.08; P=0.011), whereas no such association was found in women. Conclusions: The risk of cardiac events in LQT2 carriers with normal QTc is associated with abnormal T-wave morphology in women and pore location of mutation in men. The findings further indicate sex-specific differences in phenotype and genotype relationship in LQT2 patients.</p>},
  articleno    = {e005918},
  author       = {Platonov, Pyotr G. and McNitt, Scott and Polonsky, Bronislava and Rosero, Spencer Z. and Kutyifa, Valentina and Huang, Allison and Moss, Arthur J. and Zareba, Wojciech},
  issn         = {1941-3149},
  keyword      = {genotype,long-QT syndrome,mutation,risk,sex},
  language     = {eng},
  number       = {7},
  publisher    = {Lippincott Williams & Wilkins},
  series       = {Circulation: Arrhythmia and Electrophysiology},
  title        = {Risk Stratification of Type 2 Long-QT Syndrome Mutation Carriers with Normal QTc Interval : The Value of Sex, T-Wave Morphology, and Mutation Type},
  url          = {http://dx.doi.org/10.1161/CIRCEP.117.005918},
  volume       = {11},
  year         = {2018},
}