Gene-Specific Therapy With Mexiletine Reduces Arrhythmic Events in Patients With Long QT Syndrome Type 3

Abstract

Background: Long QT syndrome type 3 (LQT3) is a lethal disease caused by gain-of-function mutations in the SCN5A gene, coding for the alpha-subunit of the sodium channel NaV1.5. Mexiletine is used to block late sodium current and to shorten QT interval in LQT3 patients.

Objectives: The aim of this study was to determine whether mexiletine prevents arrhythmic events (arrhythmic syncope, aborted cardiac arrest, or sudden cardiac death) in LQT3 patients.

Methods: The endpoint of this retrospective cohort study, which studied consecutive LQT3 patients who were referred to our center and treated with mexiletine, was to evaluate the antiarrhythmic efficacy of mexiletine by comparing the number of arrhythmic events per patient and the annual rate of arrhythmic events during observation periods of equal duration before and after the beginning of therapy with mexiletine.

Results: The study population comprised 34 LQT3 patients, 19 (56%) of whom were male. The median age at beginning of treatment with mexiletine was 22 years, and median QTc interval before therapy 509 ms. The median duration of oral mexiletine therapy was 36 months, at an average daily dose of 8 ± 0.5 mg/kg. Mexiletine significantly shortened QTc (by 63 ± 6 ms; p < 0.0001) and reduced the percentage of patients with arrhythmic events (from 22% to 3%; p = 0.031), the mean number of arrhythmic events per patient (from 0.43 ± 0.17 to 0.03 ± 0.03; p = 0.027), and the annual rate of arrhythmic events (from 10.3% to 0.7%; p = 0.0097).

Conclusions: Besides shortening QTc interval, mexiletine caused a major reduction of life-threatening arrhythmic events in LQT3 patients, thus representing an efficacious therapeutic strategy.

Keywords: SCN5A; beta-blocker; mutation; sodium channel; sudden cardiac death.

Central Illustration

Reduction of Arrhythmic Events During Treatment With Mexiletine in Patients With Long QT Syndrome Type 3 We observed a significant reduction of the arrhythmic burden in our cohort of consecutive patients with long QT syndrome type 3 treated with mexiletine during matched periods of a median of 35 months. The percentage of patients with arrhythmic events declined from 22% (95% confidence interval [CI]: 7 to 37) to 3% (95% CI: 0 to 9; p = 0.031, A), the mean number of arrhythmic events per patient decreased from 0.43 ± 0.17 to 0.03 ± 0.03 (p = 0.027, B), and the rate of arrhythmic events dropped by 93%, from 10.3 (95% CI: 4.6 to 23) per 100 PY to 0.7 (95% CI: 0.1 to 5.5) per 100 PY (p = 0.0097, C).

Figure 1

Localization of LQT3 Mutations This illustration represents the predicted topology of the alpha subunit of the cardiac sodium channel (Nav1.5) and the position of the mutations identified in the 34 LQT3 patients who were treated with mexiletine. Blue circles = individual mutations.

Figure 2

Effect of Mexiletine on QTc Interval Values Comparison of QTc interval values for the 34 patients before (Baseline ECG) and after (First “ECG on Therapy”) starting mexiletine. Sixteen of the 22 patients (73%) with QTc values >500 ms (i.e., “high-risk QTc”, red dotted line) reduced their QTc under 500 ms after starting mexiletine (p < 0.0001). Moreover, 20 of 34 (59%) patients “normalized” their QTc values (i.e., QTc ≤460 ms, blue dotted line) after starting the drug (p < 0.0001). Patients who experienced arrhythmic events on mexiletine (asterisks) had “high-risk” QTc values while on treatment. ECG = electrocardiogram.

Figure 3

Effect of Mexiletine in 2 LQT3 Patients Upper panels (Patient A) show the effect of mexiletine in a child with a baseline QTc of 500 ms who had a syncope at the age of 1 year during fever. After starting mexiletine, his QTc shortened to 468 ms and he has remained asymptomatic for 2 years. The lower panels (Patient B) show the effect of mexiletine in a girl with a baseline QTc of 542 ms who experienced recurrent syncopal events while receiving nadolol. On mexiletine, the QTc shortened to 427 ms and she remained asymptomatic for 7 years. The beats used to measure the electrocardiographic parameters before and after starting mexiletine are indicated by the dotted lines (black for the RR interval, red for the QT interval).