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J Am Coll Cardiol. 2018 Apr 17;71(15):1663-1671. doi: 10.1016/j.jacc.2018.01.078.

Interplay Between Genetic Substrate, QTc Duration, and Arrhythmia Risk in Patients With Long QT Syndrome.

Author information

1
Molecular Cardiology, Istituti Clinici Scientifici Maugeri, Istituto di Ricovero e Cura a Carattere Scientifico, Pavia, Italy; Department of Molecular Medicine, University of Pavia, Pavia, Italy.
2
Molecular Cardiology, Istituti Clinici Scientifici Maugeri, Istituto di Ricovero e Cura a Carattere Scientifico, Pavia, Italy.
3
Department of Statistics and Quantitative Methods, University of Milan-Bicocca, Milan, Italy.
4
Molecular Cardiology, Istituti Clinici Scientifici Maugeri, Istituto di Ricovero e Cura a Carattere Scientifico, Pavia, Italy; Department of Electrical, Computer and Biomedical Engineering, University of Pavia, Pavia, Italy.
5
Health in Code, La Coruña, Spain.
6
Department of Electrical, Computer and Biomedical Engineering, University of Pavia, Pavia, Italy.
7
Molecular Cardiology, Istituti Clinici Scientifici Maugeri, Istituto di Ricovero e Cura a Carattere Scientifico, Pavia, Italy; Department of Molecular Medicine, University of Pavia, Pavia, Italy; Molecular Cardiology, Fundación Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain. Electronic address: silvia.priori@icsmaugeri.it.

Abstract

BACKGROUND:

Long QT syndrome (LQTS) is a common inheritable arrhythmogenic disorder, often secondary to mutations in the KCNQ1, KCNH2, and SCN5A genes. The disease is characterized by a prolonged ventricular repolarization (QTc interval) that confers susceptibility to life-threatening arrhythmic events (LAEs).

OBJECTIVES:

This study sought to create an evidence-based risk stratification scheme to personalize the quantification of the arrhythmic risk in patients with LQTS.

METHODS:

Data from 1,710 patients with LQTS followed up for a median of 7.1 years (interquartile range [IQR]: 2.7 to 13.4 years) were analyzed to estimate the 5-year risk of LAEs based on QTc duration and genotype and to assess the antiarrhythmic efficacy of beta-blockers.

RESULTS:

The relationship between QTc duration and risk of events was investigated by comparison of linear and cubic spline models, and the linear model provided the best fit. The 5-year risk of LAEs while patients were off therapy was then calculated in a multivariable Cox model with QTc and genotype considered as independent factors. The estimated risk of LAEs increased by 15% for every 10-ms increment of QTc duration for all genotypes. Intergenotype comparison showed that the risk for patients with LQT2 and LQT3 increased by 130% and 157% at any QTc duration versus patients with LQT1. Analysis of response to beta-blockers showed that only nadolol reduced the arrhythmic risk in all genotypes significantly compared with no therapy (hazard ratio: 0.38; 95% confidence interval: 0.15 to 0.93; p = 0.03).

CONCLUSIONS:

The study provides an estimator of risk of LAEs in LQTS that allows a granular estimate of 5-year arrhythmic risk and demonstrate the superiority of nadolol in reducing the risk of LAEs in LQTS.

KEYWORDS:

beta-blockers; genetics; inherited arrhythmias; life-threatening arrhythmic events; long QT syndrome; sudden cardiac death

PMID:
29650123
DOI:
10.1016/j.jacc.2018.01.078

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