Mutations in cytoplasmic loops of the KCNQ1 channel and the risk of life-threatening events: Implications for mutation-specific response to β-blocker therapy in type 1 long-QT syndrome

Alon Barsheshet, Ilan Goldenberg, Jin O-Uchi, Arthur J. Moss, Christian Jons, Wataru Shimizu, Arthur A. Wilde, Scott McNitt, Derick R. Peterson, Wojciech Zareba, Jennifer L. Robinson, Michael J. Ackerman, Michael Cypress, Daniel A. Gray, Nynke Hofman, Jorgen K. Kanters, Elizabeth S. Kaufman, Pyotr G. Platonov, Ming Qi, Jeffrey A. TowbinG. Michael Vincent, Coeli M. Lopes

Research output: Contribution to journalArticle

119 Scopus citations

Abstract

Background-β-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 β-adrenergic stimulation and clinical response to β-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). β-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 β-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 β-blockers. Reduced channel activation after sympathetic activation can explain the increased clinical risk and response to therapy in patients with C-loop mutations.

Original languageEnglish (US)
Pages (from-to)1988-1996
Number of pages9
JournalCirculation
Volume125
Issue number16
DOIs
StatePublished - Apr 24 2012

Keywords

  • adrenergic beta-antagonists
  • ion channels
  • long QT syndrome
  • mutation

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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    Barsheshet, A., Goldenberg, I., O-Uchi, J., Moss, A. J., Jons, C., Shimizu, W., Wilde, A. A., McNitt, S., Peterson, D. R., Zareba, W., Robinson, J. L., Ackerman, M. J., Cypress, M., Gray, D. A., Hofman, N., Kanters, J. K., Kaufman, E. S., Platonov, P. G., Qi, M., ... Lopes, C. M. (2012). Mutations in cytoplasmic loops of the KCNQ1 channel and the risk of life-threatening events: Implications for mutation-specific response to β-blocker therapy in type 1 long-QT syndrome. Circulation, 125(16), 1988-1996. https://doi.org/10.1161/CIRCULATIONAHA.111.048041