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

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          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.

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          Most cited references10

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          SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome.

          Long QT syndrome (LQT) is an inherited disorder that causes sudden death from cardiac arrhythmias, specifically torsade de pointes and ventricular fibrillation. We previously mapped three LQT loci: LQT1 on chromosome 11p15.5, LQT2 on 7q35-36, and LQT3 on 3p21-24. Here we report genetic linkage between LQT3 and polymorphisms within SCN5A, the cardiac sodium channel gene. Single strand conformation polymorphism and DNA sequence analyses reveal identical intragenic deletions of SCN5A in affected members of two unrelated LQT families. The deleted sequences reside in a region that is important for channel inactivation. These data suggest that mutations in SCN5A cause chromosome 3-linked LQT and indicate a likely cellular mechanism for this disorder.
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            Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias.

            The congenital long-QT syndrome (LQTS) is caused by mutations on several genes, all of which encode cardiac ion channels. The progressive understanding of the electrophysiological consequences of these mutations opens unforeseen possibilities for genotype-phenotype correlation studies. Preliminary observations suggested that the conditions ("triggers") associated with cardiac events may in large part be gene specific. We identified 670 LQTS patients of known genotype (LQT1, n=371; LQT2, n=234; LQT3, n=65) who had symptoms (syncope, cardiac arrest, sudden death) and examined whether 3 specific triggers (exercise, emotion, and sleep/rest without arousal) differed according to genotype. LQT1 patients experienced the majority of their events (62%) during exercise, and only 3% occurred during rest/sleep. These percentages were almost reversed among LQT2 and LQT3 patients, who were less likely to have events during exercise (13%) and more likely to have events during rest/sleep (29% and 39%). Lethal and nonlethal events followed the same pattern. Corrected QT interval did not differ among LQT1, LQT2, and LQT3 patients (498, 497, and 506 ms, respectively). The percent of patients who were free of recurrence with ss-blocker therapy was higher and the death rate was lower among LQT1 patients (81% and 4%, respectively) than among LQT2 (59% and 4%, respectively) and LQT3 (50% and 17%, respectively) patients. Life-threatening arrhythmias in LQTS patients tend to occur under specific circumstances in a gene-specific manner. These data allow new insights into the mechanisms that relate the electrophysiological consequences of mutations on specific genes to clinical manifestations and offer the possibility of complementing traditional therapy with gene-specific approaches.
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              Association of long QT syndrome loci and cardiac events among patients treated with beta-blockers.

              Data on the efficacy of beta-blockers in the 3 most common genetic long QT syndrome (LQTS) loci are limited. To describe and assess outcome in a large systematically genotyped population of beta-blocker-treated LQTS patients. Consecutive LQTS-genotyped patients (n = 335) in Italy treated with beta-blockers for an average of 5 years. Cardiac events (syncope, ventricular tachycardia/torsades de pointes, cardiac arrest, and sudden cardiac death) while patients received beta-blocker therapy according to genotype. Cardiac events among patients receiving beta-blocker therapy occurred in 19 of 187 (10%) LQT1 patients, 27 of 120 (23%) LQT2 patients, and 9 of 28 (32%) LQT3 patients (P<.001). The risk of cardiac events was higher among LQT2 (adjusted relative risk, 2.81; 95% confidence interval [CI], 1.50-5.27; P =.001) and LQT3 (adjusted relative risk, 4.00; 95% CI, 2.45-8.03; P<.001) patients than among LQT1 patients, suggesting inadequate protection from beta-blocker therapy. Other important predictors of risk were a QT interval corrected for heart rate that was more than 500 ms in patients receiving therapy (adjusted relative risk, 2.01; 95% CI, 1.16-3.51; P =.01) and occurrence of a first cardiac event before the age of 7 years (adjusted RR, 4.34; 95% CI, 2.35-8.03; P<.001). Among patients with genetic LQTS treated with beta-blockers, there is a high rate of cardiac events, particularly among patients with LQT2 and LQT3 genotypes.
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                Author and article information

                Contributors
                Journal
                J Am Coll Cardiol
                J. Am. Coll. Cardiol
                Journal of the American College of Cardiology
                Elsevier Biomedical
                0735-1097
                1558-3597
                08 March 2016
                08 March 2016
                : 67
                : 9
                : 1053-1058
                Affiliations
                [a ]Molecular Cardiology, IRCCS Salvatore Maugeri Foundation, Pavia, Italy
                [b ]Department of Statistics and Quantitative Methods, University of Milan-Bicocca, Milan, Italy
                [c ]Division of Pediatric Cardiology, Primary Children's Hospital and University of Utah, Salt Lake City, Utah
                [d ]Department of Molecular Medicine, University of Pavia, Pavia, Italy
                Author notes
                [] Reprint requests and correspondence: Dr. Silvia G. Priori, Molecular Cardiology–IRCCS Salvatore Maugeri Foundation, University of Pavia, Via Maugeri, 10–27100 Pavia, Italy.Molecular Cardiology–IRCCS Salvatore Maugeri Foundation, University of PaviaVia Maugeri10–27100 PaviaItaly silvia.priori@ 123456fsm.it
                Article
                S0735-1097(16)00009-7
                10.1016/j.jacc.2015.12.033
                4773513
                26940925
                a7161947-bf53-4b54-a69c-2d27965067ec
                © 2016 Elsevier Inc. All rights reserved.
                History
                : 8 September 2015
                : 16 November 2015
                : 14 December 2015
                Categories
                Original Investigation

                Cardiovascular Medicine
                beta-blocker,mutation,scn5a,sodium channel,sudden cardiac death,ci, confidence interval,ecg, electrocardiogram,lqt3, long qt syndrome type 3,lqts, long qt syndrome

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