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Mutations in Cytoplasmic Loops of the KCNQ1 Channel and the Risk of Life-Threatening Events Implications for Mutation-Specific Response to beta-Blocker Therapy in Type 1 Long-QT Syndrome

Barsheshet, Alon; Goldenberg, Ilan; O-Uchi, Jin; Moss, Arthur J.; Jons, Christian; Shimizu, Wataru; Wilde, Arthur A.; McNitt, Scott; Peterson, Derick R. and Zareba, Wojciech, et al. (2012) In Circulation 125(16). p.1988-1988
Abstract
Background-beta-Adrenergic stimulation is the main trigger for cardiac events in type 1 long-QT syndrome (LQT1). We evaluated a possible association between ion channel response to beta-adrenergic stimulation and clinical response to beta-blocker therapy according to mutation location. Methods and Results-The study sample comprised 860 patients with genetically confirmed mutations in the KCNQ1 channel. Patients were categorized into carriers of missense mutations located in the cytoplasmic loops (C loops), membrane-spanning domain, C/N terminus, and nonmissense mutations. There were 27 aborted cardiac arrest and 78 sudden cardiac death events from birth through 40 years of age. After multivariable adjustment for clinical factors, the... (More)
Background-beta-Adrenergic stimulation is the main trigger for cardiac events in type 1 long-QT syndrome (LQT1). We evaluated a possible association between ion channel response to beta-adrenergic stimulation and clinical response to beta-blocker therapy according to mutation location. Methods and Results-The study sample comprised 860 patients with genetically confirmed mutations in the KCNQ1 channel. Patients were categorized into carriers of missense mutations located in the cytoplasmic loops (C loops), membrane-spanning domain, C/N terminus, and nonmissense mutations. There were 27 aborted cardiac arrest and 78 sudden cardiac death events from birth through 40 years of age. After multivariable adjustment for clinical factors, the presence of C-loop mutations was associated with the highest risk for aborted cardiac arrest or sudden cardiac death (hazard ratio versus nonmissense mutations = 2.75; 95% confidence interval, 1.29-5.86; P=0.009). beta-Blocker therapy was associated with a significantly greater reduction in the risk of aborted cardiac arrest or sudden cardiac death among patients with C-loop mutations than among all other patients (hazard ratio=0.12; 95% confidence interval, 0.02-0.73; P=0.02; and hazard ratio=0.82; 95% confidence interval, 0.31-2.13; P=0.68, respectively; P for interaction=0.04). Cellular expression studies showed that membrane spanning and C-loop mutations produced a similar decrease in current, but only C-loop mutations showed a pronounced reduction in channel activation in response to beta-adrenergic stimulation. Conclusions-Patients with C-loop missense mutations in the KCNQ1 channel exhibit a high risk for life-threatening events and derive a pronounced benefit from treatment with beta-blockers. Reduced channel activation after sympathetic activation can explain the increased clinical risk and response to therapy in patients with C-loop mutations. (Circulation. 2012; 125: 1988-1996.) (Less)
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published
subject
keywords
adrenergic beta-antagonists, ion channels, long QT syndrome, mutation
in
Circulation
volume
125
issue
16
pages
1988 - 1988
publisher
Lippincott Williams and Wilkins
external identifiers
  • wos:000306955300019
  • scopus:84860210760
ISSN
1524-4539
DOI
10.1161/CIRCULATIONAHA.111.048041
language
English
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yes
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af37cd31-78d2-4316-98fd-897da1af3fd5 (old id 3079731)
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2012-10-05 07:16:18
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2017-11-12 03:43:02
@article{af37cd31-78d2-4316-98fd-897da1af3fd5,
  abstract     = {Background-beta-Adrenergic stimulation is the main trigger for cardiac events in type 1 long-QT syndrome (LQT1). We evaluated a possible association between ion channel response to beta-adrenergic stimulation and clinical response to beta-blocker therapy according to mutation location. Methods and Results-The study sample comprised 860 patients with genetically confirmed mutations in the KCNQ1 channel. Patients were categorized into carriers of missense mutations located in the cytoplasmic loops (C loops), membrane-spanning domain, C/N terminus, and nonmissense mutations. There were 27 aborted cardiac arrest and 78 sudden cardiac death events from birth through 40 years of age. After multivariable adjustment for clinical factors, the presence of C-loop mutations was associated with the highest risk for aborted cardiac arrest or sudden cardiac death (hazard ratio versus nonmissense mutations = 2.75; 95% confidence interval, 1.29-5.86; P=0.009). beta-Blocker therapy was associated with a significantly greater reduction in the risk of aborted cardiac arrest or sudden cardiac death among patients with C-loop mutations than among all other patients (hazard ratio=0.12; 95% confidence interval, 0.02-0.73; P=0.02; and hazard ratio=0.82; 95% confidence interval, 0.31-2.13; P=0.68, respectively; P for interaction=0.04). Cellular expression studies showed that membrane spanning and C-loop mutations produced a similar decrease in current, but only C-loop mutations showed a pronounced reduction in channel activation in response to beta-adrenergic stimulation. Conclusions-Patients with C-loop missense mutations in the KCNQ1 channel exhibit a high risk for life-threatening events and derive a pronounced benefit from treatment with beta-blockers. Reduced channel activation after sympathetic activation can explain the increased clinical risk and response to therapy in patients with C-loop mutations. (Circulation. 2012; 125: 1988-1996.)},
  author       = {Barsheshet, Alon and Goldenberg, Ilan and O-Uchi, Jin and Moss, Arthur J. and Jons, Christian and Shimizu, Wataru and Wilde, Arthur A. and McNitt, Scott and Peterson, Derick R. and Zareba, Wojciech and Robinson, Jennifer L. and Ackerman, Michael J. and Cypress, Michael and Gray, Daniel A. and Hofman, Nynke and Kanters, Jorgen K. and Kaufman, Elizabeth S. and Platonov, Pyotr and Qi, Ming and Towbin, Jeffrey A. and Vincent, G. Michael and Lopes, Coeli M.},
  issn         = {1524-4539},
  keyword      = {adrenergic beta-antagonists,ion channels,long QT syndrome,mutation},
  language     = {eng},
  number       = {16},
  pages        = {1988--1988},
  publisher    = {Lippincott Williams and Wilkins},
  series       = {Circulation},
  title        = {Mutations in Cytoplasmic Loops of the KCNQ1 Channel and the Risk of Life-Threatening Events Implications for Mutation-Specific Response to beta-Blocker Therapy in Type 1 Long-QT Syndrome},
  url          = {http://dx.doi.org/10.1161/CIRCULATIONAHA.111.048041},
  volume       = {125},
  year         = {2012},
}