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

Christian Jons; Jin O-Uchi; Arthur J Moss; Matthias Reumann; John J Rice; Ilan Goldenberg; Wojciech Zareba; Arthur A M Wilde; Wataru Shimizu; Jørgen K. Kanters; Scott McNitt; Nynke Hofman; Jennifer L Robinson; Coeli M B Lopes

doi:10.1126/scitranslmed.3001551

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

Christian Jons, Jin O-Uchi, Arthur J Moss, Matthias Reumann, John J Rice, Ilan Goldenberg, Wojciech Zareba, Arthur A M Wilde, Wataru Shimizu, Jørgen K. Kanters, Scott McNitt, Nynke Hofman, Jennifer L Robinson, Coeli M B Lopes

Physiology of circulation, kidney and lung

36 Citations (Scopus)

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.

Original language	English
Journal	Science Translational Medicine
Volume	3
Issue number	76
Pages (from-to)	76ra28
Number of pages	13
ISSN	1946-6234
DOIs	https://doi.org/10.1126/scitranslmed.3001551
Publication status	Published - 30 Mar 2011

Keywords

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

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Jons, C., O-Uchi, J., Moss, A. J., Reumann, M., Rice, J. J., Goldenberg, I., Zareba, W., Wilde, A. A. M., Shimizu, W., Kanters, J. K., McNitt, S., Hofman, N., Robinson, J. L., & Lopes, C. M. B. (2011). Use of mutant-specific ion channel characteristics for risk stratification of long QT syndrome patients. Science Translational Medicine, 3(76), 76ra28. https://doi.org/10.1126/scitranslmed.3001551

Jons, C, O-Uchi, J, Moss, AJ, Reumann, M, Rice, JJ, Goldenberg, I, Zareba, W, Wilde, AAM, Shimizu, W, Kanters, JK, McNitt, S, Hofman, N, Robinson, JL & Lopes, CMB 2011, 'Use of mutant-specific ion channel characteristics for risk stratification of long QT syndrome patients', Science Translational Medicine, vol. 3, no. 76, pp. 76ra28. https://doi.org/10.1126/scitranslmed.3001551

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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 (IKs) 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.",

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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

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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 (IKs) 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.

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 (IKs) 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.

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KW - Animals

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KW - Child, Preschool

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KW - Humans

KW - Infant

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KW - KCNQ1 Potassium Channel

KW - Kaplan-Meier Estimate

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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

SN - 1946-6234

VL - 3

SP - 76ra28

JO - Science Translational Medicine

JF - Science Translational Medicine

IS - 76

ER -

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

Abstract

Keywords

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