Forgot Password

If you have forgotten your password you can enter your email here and get a temporary password sent to your email.

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.

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.

Pubmed ID: 22456477


  • Barsheshet A
  • Goldenberg I
  • O-Uchi J
  • Moss AJ
  • Jons C
  • Shimizu W
  • Wilde AA
  • McNitt S
  • Peterson DR
  • Zareba W
  • Robinson JL
  • Ackerman MJ
  • Cypress M
  • Gray DA
  • Hofman N
  • Kanters JK
  • Kaufman ES
  • Platonov PG
  • Qi M
  • Towbin JA
  • Vincent GM
  • Lopes CM



Publication Data

April 24, 2012

Associated Grants

  • Agency: NHLBI NIH HHS, Id: HL-33843
  • Agency: NHLBI NIH HHS, Id: HL-51618
  • Agency: NHLBI NIH HHS, Id: R01 HL033843
  • Agency: NHLBI NIH HHS, Id: R01 HL051618

Mesh Terms

  • Adolescent
  • Adrenergic beta-Antagonists
  • Adult
  • Child
  • Female
  • Genetic Predisposition to Disease
  • Heart Arrest
  • Humans
  • KCNQ1 Potassium Channel
  • Male
  • Mutation
  • Risk
  • Romano-Ward Syndrome
  • Treatment Outcome
  • Young Adult