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Prognostic implications of mutation-specific QTc standard deviation in congenital long QT syndrome

Mathias, Andrew ; Moss, Arthur J. ; Lopes, Coeli M. ; Barsheshet, Alon ; McNitt, Scott ; Zareba, Wojciech ; Robinson, Jennifer L. ; Locati, Emanuela H. ; Ackerman, Michael J. and Benhorin, Jesaia , et al. (2013) In Heart Rhythm 10(5). p.720-725
Abstract
BACKGROUND Individual corrected QT interval (QTc) may vary widely among carriers of the same long QT syndrome (LOTS) mutation. Currently, neither the mechanism nor the implications of this variable penetrance are well understood. OBJECTIVES To hypothesize that the assessment of QTc variance in patients with congenital LOTS who carry the same mutation provides incremental prognostic information on the patient-specific QTc. METHODS The study population comprised 1206 patients with LOTS with 95 different mutations and >= 5 individuals who carry the same mutation. Multivariate Cox proportional hazards regression analysis was used to assess the effect of mutation-specific standard deviation of QTc (QTcSD) on the risk of cardiac events... (More)
BACKGROUND Individual corrected QT interval (QTc) may vary widely among carriers of the same long QT syndrome (LOTS) mutation. Currently, neither the mechanism nor the implications of this variable penetrance are well understood. OBJECTIVES To hypothesize that the assessment of QTc variance in patients with congenital LOTS who carry the same mutation provides incremental prognostic information on the patient-specific QTc. METHODS The study population comprised 1206 patients with LOTS with 95 different mutations and >= 5 individuals who carry the same mutation. Multivariate Cox proportional hazards regression analysis was used to assess the effect of mutation-specific standard deviation of QTc (QTcSD) on the risk of cardiac events (comprising syncope, aborted cardiac arrest, and sudden cardiac death) from birth through age 40 years in the total population and by genotype. RESULTS Assessment of mutation-specific QTcSD showed large differences among carriers of the same mutations (median QTcSD 45 ms). Multivariate analysis showed that each 20 ms increment in QTcSD was associated with a significant 33% (P=.002) increase in the risk of cardiac events after adjustment for the patient-specific QTc duration and the family effect on QTc. The risk associated with QTcSD was pronounced among patients with long QT syndrome type 1 (hazard ratio 1.55 per 20 ms increment; P<.001), whereas among patients with long QT syndrome type 2, the risk associated with QTcSD was not statistically significant (hazard ratio 0.99; P=.95; P value for QTcSD-by-genotype interaction=.002). CONCLUSIONS Our findings suggest that mutations with a wider variation in QTc duration are associated with increased risk of cardiac events. These findings appear to be genotype-specific, with a pronounced effect among patients with the long QT syndrome type 1 genotype. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Long QT syndrome, Corrected QT interval, Sudden cardiac death
in
Heart Rhythm
volume
10
issue
5
pages
720 - 725
publisher
Elsevier
external identifiers
  • wos:000318671200025
  • scopus:84876547836
  • pmid:23369741
ISSN
1547-5271
DOI
10.1016/j.hrthm.2013.01.032
language
English
LU publication?
yes
id
b9c79f98-6313-4a51-8de4-b837b6f1895d (old id 3815466)
date added to LUP
2016-04-01 10:14:23
date last changed
2022-01-25 21:11:09
@article{b9c79f98-6313-4a51-8de4-b837b6f1895d,
  abstract     = {{BACKGROUND Individual corrected QT interval (QTc) may vary widely among carriers of the same long QT syndrome (LOTS) mutation. Currently, neither the mechanism nor the implications of this variable penetrance are well understood. OBJECTIVES To hypothesize that the assessment of QTc variance in patients with congenital LOTS who carry the same mutation provides incremental prognostic information on the patient-specific QTc. METHODS The study population comprised 1206 patients with LOTS with 95 different mutations and &gt;= 5 individuals who carry the same mutation. Multivariate Cox proportional hazards regression analysis was used to assess the effect of mutation-specific standard deviation of QTc (QTcSD) on the risk of cardiac events (comprising syncope, aborted cardiac arrest, and sudden cardiac death) from birth through age 40 years in the total population and by genotype. RESULTS Assessment of mutation-specific QTcSD showed large differences among carriers of the same mutations (median QTcSD 45 ms). Multivariate analysis showed that each 20 ms increment in QTcSD was associated with a significant 33% (P=.002) increase in the risk of cardiac events after adjustment for the patient-specific QTc duration and the family effect on QTc. The risk associated with QTcSD was pronounced among patients with long QT syndrome type 1 (hazard ratio 1.55 per 20 ms increment; P&lt;.001), whereas among patients with long QT syndrome type 2, the risk associated with QTcSD was not statistically significant (hazard ratio 0.99; P=.95; P value for QTcSD-by-genotype interaction=.002). CONCLUSIONS Our findings suggest that mutations with a wider variation in QTc duration are associated with increased risk of cardiac events. These findings appear to be genotype-specific, with a pronounced effect among patients with the long QT syndrome type 1 genotype.}},
  author       = {{Mathias, Andrew and Moss, Arthur J. and Lopes, Coeli M. and Barsheshet, Alon and McNitt, Scott and Zareba, Wojciech and Robinson, Jennifer L. and Locati, Emanuela H. and Ackerman, Michael J. and Benhorin, Jesaia and Kaufman, Elizabeth S. and Platonov, Pyotr and Qi, Ming and Shimizu, Wataru and Towbin, Jeffrey A. and Vincent, G. Michael and Wilde, ArthurA. M. and Zhang, Li and Goldenberg, Ilan}},
  issn         = {{1547-5271}},
  keywords     = {{Long QT syndrome; Corrected QT interval; Sudden cardiac death}},
  language     = {{eng}},
  number       = {{5}},
  pages        = {{720--725}},
  publisher    = {{Elsevier}},
  series       = {{Heart Rhythm}},
  title        = {{Prognostic implications of mutation-specific QTc standard deviation in congenital long QT syndrome}},
  url          = {{http://dx.doi.org/10.1016/j.hrthm.2013.01.032}},
  doi          = {{10.1016/j.hrthm.2013.01.032}},
  volume       = {{10}},
  year         = {{2013}},
}