Use of mutant-specific ion channel characteristics for risk stratification of long QT syndrome patients
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Use of mutant-specific ion channel characteristics for risk stratification of long QT syndrome patients. / Jons, Christian; O-Uchi, Jin; Moss, Arthur J; Reumann, Matthias; Rice, John J; Goldenberg, Ilan; Zareba, Wojciech; Wilde, Arthur A M; Shimizu, Wataru; Kanters, Jørgen K.; McNitt, Scott; Hofman, Nynke; Robinson, Jennifer L; Lopes, Coeli M B.
In: Science Translational Medicine, Vol. 3, No. 76, 30.03.2011, p. 76ra28.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Use of mutant-specific ion channel characteristics for risk stratification of long QT syndrome patients
AU - Jons, Christian
AU - O-Uchi, Jin
AU - Moss, Arthur J
AU - Reumann, Matthias
AU - Rice, John J
AU - Goldenberg, Ilan
AU - Zareba, Wojciech
AU - Wilde, Arthur A M
AU - Shimizu, Wataru
AU - Kanters, Jørgen K.
AU - McNitt, Scott
AU - Hofman, Nynke
AU - Robinson, Jennifer L
AU - Lopes, Coeli M B
PY - 2011/3/30
Y1 - 2011/3/30
N2 - 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.
AB - 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.
KW - Adolescent
KW - Adult
KW - Animals
KW - Child
KW - Child, Preschool
KW - Computer Simulation
KW - Electrophysiology
KW - Genetic Predisposition to Disease
KW - Genotype
KW - Humans
KW - Infant
KW - Ion Channel Gating
KW - KCNQ1 Potassium Channel
KW - Kaplan-Meier Estimate
KW - Long QT Syndrome
KW - Male
KW - Models, Biological
KW - Mutation
KW - Oocytes
KW - Phenotype
KW - Proportional Hazards Models
KW - Registries
KW - Risk Factors
KW - Xenopus laevis
KW - Young Adult
U2 - 10.1126/scitranslmed.3001551
DO - 10.1126/scitranslmed.3001551
M3 - Journal article
C2 - 21451124
VL - 3
SP - 76ra28
JO - Science Translational Medicine
JF - Science Translational Medicine
SN - 1946-6234
IS - 76
ER -
ID: 33910765