Use of mutant-specific ion channel characteristics for risk stratification of long QT syndrome patients

Research output: Contribution to journalJournal articleResearchpeer-review

  • Christian Jons
  • Jin O-Uchi
  • Arthur J Moss
  • Matthias Reumann
  • John J Rice
  • Ilan Goldenberg
  • Wojciech Zareba
  • Arthur A M Wilde
  • Wataru Shimizu
  • Kanters, Jørgen K.
  • Scott McNitt
  • Nynke Hofman
  • Jennifer L Robinson
  • Coeli M B Lopes
Inherited long QT syndrome (LQTS) is caused by mutations in ion channels that delay cardiac repolarization, increasing the risk of sudden death from ventricular arrhythmias. Currently, the risk of sudden death in individuals with LQTS is estimated from clinical parameters such as age, gender, and the QT interval, measured from the electrocardiogram. Even though a number of different mutations can cause LQTS, mutation-specific information is rarely used clinically. LQTS type 1 (LQT1), one of the most common forms of LQTS, is caused by mutations in the slow potassium current (I(Ks)) channel a subunit KCNQ1. We investigated whether mutation-specific changes in I(Ks) function can predict cardiac risk in LQT1. By correlating the clinical phenotype of 387 LQT1 patients with the cellular electrophysiological characteristics caused by an array of mutations in KCNQ1, we found that channels with a decreased rate of current activation are associated with increased risk of cardiac events (hazard ratio=2.02), independent of the clinical parameters usually used for risk stratification. In patients with moderate QT prolongation (a QT interval less than 500 ms), slower activation was an independent predictor for cardiac events (syncope, aborted cardiac arrest, and sudden death) (hazard ratio = 2.10), whereas the length of the QT interval itself was not. Our results indicate that genotype and biophysical phenotype analysis may be useful for risk stratification of LQT1 patients and suggest that slow channel activation is associated with an increased risk of cardiac events.
Original languageEnglish
JournalScience Translational Medicine
Issue number76
Pages (from-to)76ra28
Number of pages13
Publication statusPublished - 30 Mar 2011

    Research areas

  • Adolescent, Adult, Animals, Child, Child, Preschool, Computer Simulation, Electrophysiology, Genetic Predisposition to Disease, Genotype, Humans, Infant, Ion Channel Gating, KCNQ1 Potassium Channel, Kaplan-Meier Estimate, Long QT Syndrome, Male, Models, Biological, Mutation, Oocytes, Phenotype, Proportional Hazards Models, Registries, Risk Factors, Xenopus laevis, Young Adult

ID: 33910765