title: Use of mutant-specific ion channel characteristics for risk stratification of long QT syndrome patients.
abstract: 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 α 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.
authors: Cardiology Division, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
authors: Christian
authors: C
authors: Jons
authors: Jin
authors: J
authors: O-Uchi
authors: Arthur J
authors: AJ
authors: Moss
authors: Matthias
authors: M
authors: Reumann
authors: John J
authors: JJ
authors: Rice
authors: Ilan
authors: I
authors: Goldenberg
authors: Wojciech
authors: W
authors: Zareba
authors: Arthur A M
authors: AA
authors: Wilde
authors: Wataru
authors: W
authors: Shimizu
authors: Jorgen K
authors: JK
authors: Kanters
authors: Scott
authors: S
authors: McNitt
authors: Nynke
authors: N
authors: Hofman
authors: Jennifer L
authors: JL
authors: Robinson
authors: Coeli M B
authors: CM
authors: Lopes
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D002648:Child; D002675:Child, Preschool; D003198:Computer Simulation; D004594:Electrophysiology; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007223:Infant; D015640:Ion Channel Gating / Q000502:physiology*; D051657:KCNQ1 Potassium Channel / Q000235:genetics* / Q000378:metabolism*; D053208:Kaplan-Meier Estimate; D008133:Long QT Syndrome / Q000235:genetics* / Q000503:physiopathology*; D008297:Male; D008954:Models, Biological; D009154:Mutation; D009865:Oocytes / Q000166:cytology / Q000502:physiology; D010641:Phenotype; D016016:Proportional Hazards Models; D012042:Registries; D012307:Risk Factors; D014982:Xenopus laevis; D055815:Young Adult
chemical_list: D051657:KCNQ1 Potassium Channel