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Gene-Specific Therapy With MexiletineReduces Arrhythmic Events inPatients With Long QT Syndrome Type 3

Andrea Mazzanti, MD,a Riccardo Maragna, BS,a Alessandro Faragli, MD,a Nicola Monteforte, MD,a

Raffaella Bloise, MD,a Mirella Memmi, PHD,a Valeria Novelli, PHD,a Paola Baiardi, PHD,a Vincenzo Bagnardi, PHD,b

Susan P. Etheridge, MD,c Carlo Napolitano, MD, PHD,a Silvia G. Priori, MD, PHDa,d

ABSTRACT

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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 ¼ 0.031), the mean number of arrhythmic events per patient (from 0.43 � 0.17 to 0.03 � 0.03; p ¼ 0.027), and

the annual rate of arrhythmic events (from 10.3% to 0.7%; p ¼ 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. (J Am Coll Cardiol 2016;67:1053–8)

© 2016 by the American College of Cardiology Foundation.

L ong QT syndrome type 3 (LQT3) is a rare variantof long QT syndrome (LQTS) caused by gain-of-function mutations in the gene SCN5A, coding

for the sodium channel NaV1.5 (1). Based on reportsthat the incidence of LQTS in neonates is 1:2,000 (2)and that LQT3 accounts for approximately 10% ofLQTS patients (3), the incidence of LQT3 is estimatedat 1:20,000.

m aMolecular Cardiology, IRCCS Salvatore Maugeri Foundation, Pavia

thods, University of Milan-Bicocca, Milan, Italy; cDivision of Pediatric Card

ah, Salt Lake City, Utah; and the dDepartment of Molecular Medicine, Univ

Telethon grant N. GGP11141, by an unrestricted research grant by Gilead,

lian Ministry of Health. Dr. Priori has received research funds from Gilead

ationships relevant to the contents of this paper to disclose.

nuscript received September 8, 2015; revised manuscript received Novem

LQT3 is characterized by a severe prognosis(3,4) and an incomplete response to beta-blockers(5), as compared to LQTS type 1, the most com-mon LQTS variant. Since arrhythmic events inLQT3 occur predominantly at rest (6), the valueof beta-blocker therapy has been questioned(5,7), leaving the management of LQT3 patientsuncertain.

, Italy; bDepartment of Statistics and Quantitative

iology, Primary Children’s Hospital and University of

ersity of Pavia, Pavia, Italy. This work was supported

and by the Ricerca Corrente Funding scheme of the

. All other authors have reported that they have no

ber 16, 2015, accepted December 14, 2015.

ABBR EV I A T I ON S

AND ACRONYMS

CI = confidence interval

ECG = electrocardiogram

LQT3 = long QT syndrome

type 3

LQTS = long QT syndrome

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This study is an extension of 2 pilot workswe conducted in the late 1990s, when wedemonstrated the ability of mexiletine toabbreviate the duration of ventricular repo-larization in an animal model of LQT3 (8) andin LQT3 patients (9). Those preliminary ob-servations led to an off-label use of mex-iletine in LQT3 patients, targeted to shorten

the QT interval; this off-label use is now recom-mended in clinical practice guidelines (10). Unfor-tunately, there is no evidence to support thehypothesis that, by shortening the QTc, this drugmay also reduce the occurrence of life-threateningarrhythmias.

The objective of the study was to evaluate theability of mexiletine to reduce the occurrence ofarrhythmic events in LQT3 patients.

METHODS

We enrolled consecutive LQT3 patients referred to ourcenter who accepted treatment with oral mexiletine.For each individual, we collected demographic data,personal and family history, symptoms, arrhythmicevents, and therapy at follow-up, which was thenstored in a customized database. Additionally, westored electrocardiogram (ECG) parameters forrhythm, heart rate, and duration of PR, QRS, and QTintervals. In addition, we obtained 12-lead ECGs (paperspeed 25 mm/s and 10 mm/mV sensitivity) at stableheart rates close to 60 beats/min during daylight hoursto limit the confounding effect of diurnal variability ofQT interval (11). The QT interval duration before andafter therapy was measured in lead II, selecting beatspreceded by similar RR intervals, as required whenapplying Bazett’s formula.

SEE PAGE 1059

TERMS AND DEFINITIONS. Arrhythmic events includedsudden cardiac death, aborted cardiac arrest(including appropriate implantable cardioverter-defibrillator [ICD] shocks), or syncope occurring in theabsence of alternative explanations (e.g., orthostatichypotension or vagally mediated episodes).

Symptomatic patients were defined as individualswho had experienced $1 arrhythmic event(s) beforestarting mexiletine.

We used several electrocardiographic terms. Base-line ECG was the ECG recorded at first visit, beforestarting mexiletine. ECG on therapy was used todescribe the first ECG recorded after initiation ofmexiletine, when the maximum-tolerated dose ofmexiletine was administered. To verify whether theeffect of mexiletine was maintained across the 24-h

period, we added measurements of ECG parametersfrom the first Holter monitor recording obtained atour center on therapy, comparing QTc duration dur-ing “daytime” hours (at a heart rate of 60 beats/min)versus QTc duration at the slowest heart rate recor-ded during “night time.”

STATISTICAL ANALYSIS. Statistical analysis wasperformed using SPSS software version 21 (IBM Corp.,Armonk, New York). Continuous variables wereexpressed as median with interquartile range (IQR) ormean � SE; comparisons were performed using pairedand unpaired nonparametric tests as appropriate.Categorical variables were reported as absolute andrelative frequencies and compared by Fisher exact orMcNemar tests.

To evaluate the antiarrhythmic efficacy of mex-iletine, a matched-period analysis was performed tocompare arrhythmic events off and on mexiletine(12). For each patient, periods of equal durationbefore and after starting mexiletine were identified,with patients serving as their own controls. Twoinfants who initiated therapy in the first week of lifewere considered ineligible for the matched-periodanalysis because they had a pre-drug observationtime of only 7 days; therefore, the analysis was con-ducted on 32 patients.

The number of arrhythmic events was determinedfor thematched periods and averaged over the numberof patients. To assess the effect of mexiletine on eventrates, a Poisson regression model was fitted usinggeneralized estimating equations. Robust standarderrors were computed to account for intrapatient cor-relation. The incidence rate ratio with 95% confidenceinterval (CI) was calculated to measure the impact ofmexiletine on event counts over time. A value of p <

0.05 (2 sides) was considered statistically significant.

RESULTS

POPULATION CHARACTERISTICS. A total of 34 LQT3patients (19 or 56% males) were enrolled. The muta-tions identified in the cohort are shown in Figure 1.Patients entered the study at the time of the firstclinical visit to our center and the total observationtime was 59 months (IQR: 29 to 144 months). Mex-iletine was initiated at a median age of 22 years(IQR: 8 to 44 years); the median QTc at baseline ECGwas 509 ms (IQR: 490 to 548 ms). Five infantsyounger than 1 year of age were referred to our centerafter experiencing a cardiac arrest (4 of 5) or a pro-longed loss of consciousness (1 of 5); all of them had aQTc interval >550 ms.

Before starting mexiletine, 21 of 34 (62%) in-dividuals were asymptomatic and 13 (38%) were

FIGURE 1 Localization of LQT3 Mutations

NH2

COOHI397FV411M

L771V S941N P1332L DelQKP1507-1509

R1623QR1626PR1644HM1652R

E1784K

D I D II D III D IV

S1 S2 S3 S4 S5 S6 S1 S2 S3 S4 S5 S6 S1 S2 S3 S4 S5 S6 S1 S2 S3 S5 S6

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 ¼ individual mutations.

FIGURE 2 Effect of Mexiletine on QTc Interval Values

700

650

600

550

500

450

400

460

Baseline ECG First “ECG on Therapy”

QTc

Inte

rval

(ms)

22/34 patientswith QTc > 500 ms

0 patientswith QTc ≤ 460 ms

*** 6/34 patients

with QTc > 500 ms

20/34 patientswith QTc ≤ 460 ms

p < 0.0001

p < 0.0001

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 ¼ electrocardiogram.

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symptomatic. Among the symptomatic patients,7 had experienced $1 cardiac arrest: 4 while onbeta-blockers and 3 while off therapy. At the time ofmexiletine initiation, 21 of 34 (62%) patients were onchronic beta-blocker therapy.

EFFECT OF MEXILETINE TREATMENT. Mexiletinewas administered in the 34 patients at a mean dose of8 � 0.5 mg/kg/day; the median QTc at the first ECG ontherapy was 457 ms (IQR: 434 to 481 ms). Mexiletineinduced a mean shortening of the QTc interval of 63 �6 ms (p < 0.0001) (Figures 2 and 3). Before startingmexiletine, 22 of 34 (65%) patients had QTc values>500 ms, and 16 of 22 (73%) reduced their QTc underthis high-risk threshold (3) after drug initiation(p < 0.0001). Moreover, 20 of 34 (59%) patientsexhibited “normal” QTc values (i.e., QTc #460 ms)after starting mexiletine (p < 0.0001) (Figure 2).

There was no statistically significant differencebetween median QTc values on mexiletine duringdaytime (464 ms; IQR: 450 to 510 ms) or night time(448 ms; IQR: 432 to 505 ms; p ¼ 0.354). There wasalso no statistically significant difference betweenmedian QTc values on the first “ECG on therapy” andat last follow-up (p ¼ 0.234).

None of the 21 patients who were asymptomaticbefore mexiletine experienced arrhythmic events af-ter initiating the drug. Among the 13 patients whowere symptomatic before mexiletine, 10 remainedsymptom-free while receiving the drug, whereas 3patients experienced arrhythmic events on mex-iletine (indicated by an asterisk in Figure 2); all 3 had

experienced arrhythmic storms in the first 2 monthsof life while on beta blockade. The first infantreceived mexiletine in conjunction with an ICD anddied from an arrhythmic storm unresponsive to ICDshocks after 11 months of treatment. The second child

FIGURE 3 Effect of Mexiletine in 2 LQT3 Patients

Patient A

Pre: RR 1040ms, QT/QTc 510/500 ms Post: RR 1050ms, QT/QTc 480/468 ms

DII

V5

RR

QT DII

V5

RR

QT

Patient B

Pre: RR 920ms, QT/QTc 520/542 ms Post: RR 920ms, QT/QTc 410/427 ms

II

V5

RR

QTDII

V5

RR

QT

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).

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had a cardiac arrest during fever 2 weeks after start-ing mexiletine and was resuscitated. The thirdpatient, despite responding initially to mexiletine(13), subsequently demonstrated prolonged QTinterval again (14) and died at 4 years. All 3 infantsshowed extreme QTc prolongation before mexiletine,greatly exceeding 500 ms on treatment (607, 586, and592 ms) (Figure 2).

Using 12-lead Holter monitor recording, we verifiedthat no patient developed a type 1 Brugada patternwhile receiving mexiletine (15).

ARRHYTHMIC EVENTS DURING MATCHED PERIODS.

The median duration of risk exposure during matchedperiods before and after mexiletine was 35 months(IQR: 19 to 64 months), for a total of 136.2person-years per period. Using mexiletine, there wasa significant reduction in the percentage of patientswith arrhythmic events (from 22% [95% CI: 7 to 37] to3% [95% CI: 0 to 9]; p ¼ 0.031), in the mean number ofarrhythmic events per patient (from 0.43 � 0.17 to0.03 � 0.03; p ¼ 0.027), and in the rate of arrhythmicevents, which dropped by 93% (from 10.3 [95% CI:4.6 to 23] to 0.7 [95% CI: 0.1 to 5.5] per 100 PY;p ¼ 0.0097) (Central Illustration).

DISCUSSION

Several studies (5,7) reported that LQT3 patients havean excessive risk of arrhythmic events as compared toLQT1, even with beta-blocker treatment. Using anexperimental preparation of LQT3, Shimizu and Ant-zelevitch (16) speculated that beta-blockers may beproarrhythmic in LQT3 and the efficacy of these drugsin LQT3 remains undefined. For these reasons, alter-native therapeutic strategies are needed to reduce therisk of life-threatening events in LQT3 patients.

The use of sodium-channel blockers to shorten QTinterval in LQT3 therapy has been supported in recentclinical guidelines (Class IIb, Level of Evidence: C)(10) but, due to the lack of clinical data, no recom-mendation on the antiarrhythmic efficacy of mex-iletine in LQT3 was provided.

We demonstrated here for the first time that,besides shortening the QT interval (4,8,9), long-termtreatment with mexiletine reduced the occurrenceof arrhythmic events in LQT3 patients. Duringmatched-period observations of almost 3 years, boththe mean number of arrhythmic events per patientand the annual rate of arrhythmic events weresignificantly reduced.

CENTRAL ILLUSTRATION Reduction of Arrhythmic Events During Treatment With Mexiletine in PatientsWith Long QT Syndrome Type 3

A B

C

Mazzanti, A. et al. J Am Coll Cardiol. 2016; 67(9):1053–8.

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 ¼ 0.031, A), the mean number of arrhythmic events per patient decreased from 0.43 � 0.17 to 0.03 � 0.03 (p ¼ 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 ¼ 0.0097, C).

J A C C V O L . 6 7 , N O . 9 , 2 0 1 6 Mazzanti et al.M A R C H 8 , 2 0 1 6 : 1 0 5 3 – 8 Antiarrhythmic Efficacy of Mexiletine in LQT3

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Interestingly, more than two-thirds of patients(16 of 22) with “high-risk” QT intervals (3) in baselineconditions reduced their QTc to below the thresholdof 500 ms after mexiletine and more than 50% of pa-tients (20 of 34) had a normalization of QTc duration(i.e., QTc #460 ms) while on therapy (Figure 2). Theonly patients who continued to experience arrhythmicevents onmexiletine were those who, despite showinga shortening of QTc >100 ms, remained in the “high-risk” category with QTc >500 ms while on therapy.This observation suggests that the therapeutic goalshould not be related to the amount of QTc shortening,but rather to obtaining QTc values <500 ms.

Our study provided novel information on thetolerability of long-term mexiletine in young LQT3

patients including infants. Importantly, none of thepatients who were asymptomatic before mexiletineexperienced an arrhythmic event on the agent.

It is becoming increasingly difficult to find mex-iletine in several countries; in Italy the importance ofthe drug for selected groups of patients has beenrecognized and the military pharmacy started pro-ducing and selling mexiletine. Furthermore, in 2014,the Italian Medicines Agency supported our requestto provide free mexiletine to patients with LQTS.STUDY LIMITATIONS. We acknowledge that ourcohort might present a selection bias because patientswith a highly malignant form of LQT3 might havedied before receiving medical attention and beingtreated with mexiletine.

PERSPECTIVES

COMPETENCY IN MEDICAL KNOWLEDGE:

Patients with LQT3 respond incompletely to beta-

blockers and face an unfavorable prognosis. Mexile-

tine exerted effective antiarrhythmic effects in this

patient cohort, representing a genotype-specific

treatment for an inherited arrhythmogenic substrate.

COMPETENCY IN PATIENT CARE AND

PROCEDURAL SKILLS: Mexiletine therapy should

be considered for patients with LQT3 who have QTc

intervals >500 ms to reduce the risk of life-

threatening arrhythmic events.

TRANSLATIONAL OUTLOOK: Clinical trials are

needed to establish whether therapy with mexiletine

should be adopted as a standard adjunct to the care of

patients with LQT3.

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CONCLUSIONS

We reported here the first observation that a medi-cation, other than beta-blockers, is able to reduce theoccurrence of arrhythmic events in LQT3 patients,corroborating the hypothesis that mexiletine mayimprove survival in these patients. Overall, our datasupported the view that precision medicine can beapplied to the management of LQTS patients, guidingnot only risk stratification, but also the identificationof therapies able to modify the molecular mechanismof the disease.

ACKNOWLEDGMENT The authors thank KatherineUnderwood, BS, for her editorial contribution.

REPRINT REQUESTS AND CORRESPONDENCE: Dr.Silvia G. Priori, Molecular Cardiology–IRCCS Salva-tore Maugeri Foundation, University of Pavia, ViaMaugeri, 10–27100 Pavia, Italy. E-mail: silvia.priori@fsm.it.

RE F E RENCE S

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2. Schwartz PJ, Stramba-Badiale M, Crotti L, et al.Prevalence of the congenital long-QT syndrome.Circulation 2009;120:1761–7.

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4. Blaufox AD, Tristani-Firouzi M, Seslar S, et al.Congenital long QT 3 in the pediatric population.Am J Cardiol 2012;109:1459–65.

5. Priori SG, Napolitano C, Schwartz PJ, et al. As-sociation of long QT syndrome loci and cardiacevents among patients treated with beta-blockers.JAMA 2004;292:1341–4.

6. Schwartz PJ, Priori SG, Spazzolini C, et al.Genotype-phenotype correlation in the long-QTsyndrome: gene-specific triggers for life-threateningarrhythmias. Circulation 2001;103:89–95.

7. Zareba W, Moss AJ, Schwartz PJ, et al. Influenceof genotype on the clinical course of the long-QTsyndrome. International Long-QT Syndrome

Registry Research Group. N Engl J Med 1998;339:960–5.

8. Priori SG, Napolitano C, Cantu F, Brown AM,Schwartz PJ. Differential response to Naþ channelblockade, beta-adrenergic stimulation, and rapidpacing in a cellular model mimicking the SCN5Aand HERG defects present in the long-QT syn-drome. Circ Res 1996;78:1009–15.

9. Schwartz PJ, Priori SG, Locati EH, et al. Long QTsyndrome patients with mutations of the SCN5Aand HERG genes have differential responses toNaþ channel blockade and to increases in heartrate. Implications for gene-specific therapy. Cir-culation 1995;92:3381–6.

10. Priori SG, Blomstrom-Lundqvist C, Mazzanti A,et al. 2015 ESC guidelines for the management ofpatients with ventricular arrhythmias and theprevention of sudden cardiac death. Eur Heart J2015;36:2793–867.

11. Rautaharju PM, Surawicz B, Gettes LS, et al.AHA/ACCF/HRS recommendations for the stan-dardization and interpretation of the electrocar-diogram: part IV: the ST segment, T and U waves,and the QT interval: a scientific statement. J AmColl Cardiol 2009;53:982–91.

12. Moss AJ, Zareba W, Hall WJ, et al. Effective-ness and limitations of beta-blocker therapy incongenital long-QT syndrome. Circulation 2000;101:616–23.

13. Schwartz PJ, Priori SG, Dumaine R, et al.A molecular link between the sudden infant deathsyndrome and the long-QT syndrome. N Engl JMed 2000;343:262–7.

14. Ruan Y, Liu N, Bloise R, Napolitano C, Priori SG.Gating properties of SCN5A mutations and theresponse to mexiletine in long-QT syndrome type3 patients. Circulation 2007;116:1137–44.

15. Priori SG, Napolitano C, Schwartz PJ, Bloise R,Crotti L, Ronchetti E. The elusive link betweenLQT3 and Brugada syndrome: the role of flecainidechallenge. Circulation 2000;102:945–7.

16. Shimizu W, Antzelevitch C. Differential effectsof beta-adrenergic agonists and antagonists inLQT1, LQT2 and LQT3 models of the long QTsyndrome. J Am Coll Cardiol 2000;35:778–86.

KEY WORDS beta-blocker, mutation,SCN5A, sodium channel, sudden cardiacdeath