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Mexiletine Prevents RecurrentTorsades de Pointes in AcquiredLong QT Syndrome Refractory toConventional Measures

Marwan Badri, MBCHB,* Aashay Patel, MD,* Chinmay Patel, MD,* Guizhi Liu, MD,* Matthew Goldstein, MD,*Victoria M. Robinson, MBCHB,* Xiaolin Xue, MD,y Lin Yang, MD,y Peter R. Kowey, MD,*z Gan-Xin Yan, MD, PHD*yx

ABSTRACT

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OBJECTIVES The purpose of this study was to examine the role of mexiletine, a late sodium current (INa-L) blocker, in

acute termination of torsades de pointes (TdP) refractory to conventional therapy in acquired long QT syndromes (LQTS).

BACKGROUND Long QT interval can predispose to TdP and is therefore associated with significant mortality. Currently,

there is no available pharmacotherapy to target directly the ionic basis ofmost LQTS for the acute termination of TdP. Earlier

evidencehighlighted the roleof INa-L in thepathophysiologyof longQTandTdP,particularly inpatientswithcongenital LQTS.

METHODS Twelve patients with TdP caused by acquired LQTS were treated with mexiletine after failure of conventional

treatment including discontinuation of QT-prolonging drugs, intravenous administration of magnesium, and correction of

serum electrolyte abnormalities.

RESULTS No recurrence of TdP occurred within 2 h after initiation of treatment with mexiletine in all 12 patients. Macro

T-wave alternans accompanied by QT prolongation, an electrocardiographic precursor of TdP that was seen in 3 patients,

was also abolished by mexiletine. Treatment with mexiletine shortened the QTc interval from 599 � 27 ms to 514 � 16 ms

(p ¼ 0.001). The interval from the peak to the end of the T-wave (Tp-e interval) decreased from 145 � 18 ms to 106 � 9

ms (p ¼ 0.005). The Tp-e/QT ratio decreased from 0.27 � 0.02 to 0.23 � 0.018 (p ¼ 0.01). Mexiletine had no significant

effect on QRS complex duration.

CONCLUSIONS INa-L blockade with mexiletine may be an effective treatment approach to terminate refractory TdP

from several acquired causes of LQTS. (J Am Coll Cardiol EP 2015;1:315–22) © 2015 by the American College of

Cardiology Foundation.

T orsades de pointes (TdP) is a polymorphicform of ventricular tachycardia seen inthe setting of QT interval prolongation

that was first described by Dessertenne in 1966(1). Other electrocardiographic manifestations thataccompany significant QT prolongation includemacro T-wave alternans (TWA) (2). Since the firstdescription, the list of acquired pathologic condi-tions that lead to QT prolongation and TdP has

m the *Lankenau Medical Center and Lankenau Institute of Medical Resea

spital, Xi’An Jiaotong University, Xi’An, China; zJefferson Medical Col

nnsylvania; and the xAnzhen Hospital, Capital Medical University, Beijin

umia Research Foundation, the WW Smith Foundation, and the Nati

70289). The authors have reported that they have no relationships relevan

d A. Patel contributed equally to this work.

ten to this manuscript’s audio summary by JACC: Clinical Electrophysiolo

nuscript received April 14, 2015; accepted May 21, 2015.

markedly expanded. TdP is caused by eithercongenital or acquired long QT syndromes (LQTS).Whereas prescription drugs account for the major-ity of cases of acquired LQTS (3), other causesinclude post-myocardial infarction QT prolongation(4), electrolyte disturbances (hypokalemia, hypo-magnesemia, and hypocalcemia), takotsubo cardiomyo-pathy (5), pheochromocytoma (6), and intracranialbleeding (7).

rch, Wynnewood, Pennsylvania; yThe First Teaching

lege of Thomas Jefferson University, Philadelphia,

g, China. This study was supported by the Sharpe-

onal Natural Science Foundation of China (NSFC-

t to the contents of this paper to disclose. Drs. Badri

gy Editor-in-Chief Dr. David J. Wilber.

ABBR EV I A T I ON S

AND ACRONYMS

EAD = early after

depolarization

INa-L = late sodium current

LQTS = long QT syndromes

TdP = torsades de pointes

Tp-e interval = interval from

the peak to the end of the

T-wave

TWA = T-wave alternans

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First-line treatment approaches to TdPinclude removal of the offending causes, theuse of intravenous magnesium, maintenanceof high-normal serum potassium level, andavoidance of QT-prolonging agents. In somerefractory cases, isoproterenol infusion ortemporary transvenous ventricular pacingmay be required to increase heart rate,thereby to shorten the QT interval (8,9).

TdP often occurs during bradycardia orafter a long pause that exaggerates the QTinterval prolongation (10,11). Additionally,

bradycardia and pauses increase the period from thepeak to the end of the T-wave (Tp-e), which representstransmural dispersion of repolarization, during whichventricular muscle cells are most vulnerable to TdP.Recent basic research has shown that late sodium(INa-L) is the key current contributing to rate adapta-tion of ventricular repolarization (12,13). When INa-L islarge, ventricular repolarization, which is representedby the QT interval on the surface electrocardiogram(ECG), exhibits more prominent rate dependence.Conversely, delayed ventricular repolarization, irre-spective of its etiology, can amplify INa-L by slowingits inactivation and is associated with bradycardia orpause-dependent exacerbation of QT and Tp-e pro-longation (12,14). Therefore, inhibition of INa-L couldbe a common pharmacotherapeutic target for termi-nation and prevention of TdP in LQTS.

SEE PAGE 323

Mexiletine, a Class Ib antiarrhythmic drug, is apotent blocker of INa-L even at therapeutic plasmaconcentrations (IC50—half maximum inhibitoryconcentration—of INa-L by mexiletine is 17.6 � 1.9mmol/l) compared with its relatively weak effect on thefast sodium current (15,16). Mexiletine was shown inanimal models to shorten drug-induced QT prolonga-tion (17–19). Mexiletine also shortens QT interval inpatients with congenital LQT3 caused by a gain-of-function mutation in INa-L (20) and is therefore rec-ommended as an additional therapy to beta-blockers inthis subset of patients (21). However, clinical infor-mation regarding the use of an INa-L blocker in acutetermination of TdP in acquired cases of LQTS that arenot necessarily related to an increase in INa-L is lacking.Although ranolazine also blocks INa-L, it inhibits therapidly activating delayed rectifier potassium (Ikr)current and may prolong the QT interval, thus limitingthe potential of its use in this subset of patients.

Therefore, we investigated the role of INa-L

blockade with mexiletine in the acute termination ofTdP in several patients with acquired causes of LQTS.The effect of mexiletine on TWA was also studied.

METHODS

From June 2011 to February 2015, 12 consecutive pa-tients with TdP in acquired LQTS were treated withmexiletine after failure of conventional treatmentincluding discontinuation of QT-prolonging drugs,intravenous administration of magnesium, andcorrection of serum electrolyte abnormalities. Thestudy was compliant with the declaration of Helsinkiand was conducted in accordance with the policies ofthe Institutional Review Board of Lankenau MedicalCenter (Wynnewood, Pennsylvania) and the FirstTeaching Hospital of Xi’An Jiaotong University(Xi’An, China). Patients were identified by review ofelectrophysiology consultations during the studyperiod. In each case, a review of medical records andmedication administration history was performed.The most probable reason for TdP was determinedon the basis of case review by a team of 7 boardcertified electrophysiologists. Demographic, clinical,and electrocardiographic parameters were collectedfor all patients. A 12-lead ECG was obtained beforeand after the first dose of mexiletine and as needed.All inpatients were continuously monitored ontelemetry (7-lead ECG monitoring system).

Patients who developed TdP received conventionaltreatment first that included discontinuation ofQT-prolonging agents or removal of the offendingcauses, intravenous magnesium, as well as replen-ishment of serum magnesium (target: 2 to 3 mg/dl),potassium (target: 4 to 5 mEq/l), and calcium (target:9 to 10 mg/dl). Intravenous isoproterenol infusion ortemporary transvenous pacing was also used in somecases of pause-dependent TdP. Mexiletine (200 to450 mg/day orally) was administered to the patientswith refractory TdP, defined as occurring at least 2 hafter the administration of conventional therapy.

Study endpoints were as follows:

1. Treatment failure: Treatment with mexiletine wasconsidered a failure if a patient had any episode ofTdP more than 2 h after the first dose of mexiletinebecause the drug reaches peak plasma concentra-tion 2 to 4 h after oral administration (22). TdP wasdefined as polymorphic ventricular tachycardia($3 beats) in the setting of QT prolongation. Thetreatment was also considered a failure if TWApersisted after treatment with mexiletine.

2. QTc interval, Tp-e intervals, and Tp-e /QT ratio: TheQT interval in lead II/V5 or other leads with a clearlydefined T-wave end were selected for measurement.The QTc interval was calculated using Bazett’s for-mula. The Tp-e interval was measured from thepeak of the T-wave to the point where the steepest

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down-slope of T-wave intersected the isoelectricline. The QT and Tp-e intervals were measuredmanually on 3 consecutive beats without precedingectopic beats, and the mean of 3 values wasreported.

3. QT-RR relationship: The QT interval was measuredusing telemetry-monitored rhythms, and the pre-mexiletine and post-mexiletine QT-RR pairs wereplotted for calculation of the slope for each indi-vidual patient who exhibited good-quality telem-etry rhythm strips. A total of 112 pre-mexiletineQT-RR pairs and 118 post-mexiletine QT-RR pairswere obtained in 8 of 12 patients.

STATISTICAL ANALYSIS. All variables were expres-sed as mean � SEM. Changes in the pre- and post-mexiletine QTc interval, Tp-e interval, and Tp-e/QTratio were compared with 2-sided, paired t tests.The pre-mexiletine and post-mexiletine slope ofthe QT-RR was calculated on the basis of the linearregression in each individual patient. The statisticalanalysis was performed between mean values of theslopes using the paired t test.

RESULTS

Twelve patients (8 female) developed refractory TdPsecondary to acquired QT prolongation. RecurrentTdP was present at least 2 h (range: 2 to 72 h) afterconventional treatment including discontinuation of

TABLE 1 Baseline Patient Characteristics, Proposed Causes of Long Q

Description of TdP

Patient #Age (yrs)/

SexProposed Cause(s)

of Long QTBaseline QTc

(ms)Pre-mexiletine

Tp-e/QT

1 81/F Stress-inducedcardiomyopathy,amiodarone

810 0.378 2

2 73/F Amiodarone 700 0.18 1

3 58/F Amiodarone 480 0.21 1

4 76/F Amiodarone �Levofloxacin

520 0.26 1

5 66/M Amiodarone �Levofloxacin

610 0.26 1

6 85/F Dofetilide 600 0.43 1

7 63/M Dofetilide 489 0.22 2

8 74/F Dofetilide 509 0.161 1

9 72/M Dofetilide, 650 0.2 1

10 49/F Severe hypothyroidism 590 0.45 1

11 53/M Unidentified 610 0.26 1

12 66/F Stress-inducedcardiomyopathy

630 0.33 2

bid ¼ twice a day; ICD ¼ implantable cardioverter-defibrillator; TdP ¼ torsade de pointhe QT interval.

QT-prolonging drugs and correction of the offendingcauses, intravenous administration of magnesium,and correction of serum electrolyte abnormalities.Among these 12 patients, 3 patients had macro TWA.Causes of QT prolongation were drug-induced condi-tions, stress-induced cardiomyopathy, and severehypothyroidism. Baseline characteristics, proposedcauses of QT prolongation and TdP, arrhythmic mani-festation, and description of TdP are listed in Table 1.Among the 12 patients, 2 patients had TdP refractory tointravenous isoproterenol infusion, and a third pa-tient’s condition was refractory to temporary trans-venous pacing. These 12 patients were then treatedwith oral mexiletine, 150 to 450 mg/day orally.

EFFECTS OF MEXILETINE ON ACUTE TERMINATION

OF TORSADES DE POINTES. No further episodes ofTdP occurred after 2 h following the first dose ofmexiletine in all 12 patients. This antiarrhythmiceffect was accompanied by resolution of frequentR-on-T ectopic beats (n ¼ 4) and TWA (n ¼ 3)(Figure 1). Three patients had nonsustained TdPwithin the first hour after mexiletine administration.

EFFECTS OF MEXILETINE ON QTc, TP-E INTERVALS,

TP-E/QT RATIO, AND QRS DURATION. Mexiletineshortened the QTc interval from 599 � 27 ms to 514 �16 ms (p ¼ 0.001). The Tp-e interval decreased from145 � 18 ms to 106 � 9 ms (p < 0.01). The Tp-e/QT ratiodecreased from 0.27 � 0.02 to 0.23 � 0.01 (p ¼ 0.01).Four examples of this effect are displayed in Figure 2.

T, Pre- and Post-Mexiletine QTc, Tp-e/QT Ratio, Dose of Mexiletine Used, and

MexiletineDose

Post-Mexiletine QTc(ms)

Post-mexiletineTp-e/QT

Delta QTc(ms) Description of TdP

00 mg bid 552 0.291 258 More than 5 runs of 10–15 beatsfor 48 h

50 mg bid 590 0.2 110 More than 5 runs of up to 7 s

50 mg bid 430 0.16 50 More than 5 runs of up to 25 beats

50 mg bid 500 0.23 20 More than 5 runs

50 mg bid 540 0.25 70 6 episodes of sustained TdP causingICD shocks

50 mg bid 460 0.3 140 More than 5 runs of TdP lasting 2–3 s

00 mg once 446 0.18 43 More than 5 runs of TdP lasting 2–3 s

50 mg bid 482 0.165 27 More than 5 runs of TdP lasting 2–3 s

50 mg bid 620 0.17 30 More than 5 runs of TdP lasting 2–3 s

50 mg bid 520 0.28 70 10 episodes of sustained TdP despitetemporary pacing

50 mg bid 530 0.18 80 2 sustained TdP episodes requiringdefibrillation in addition tomultiple short runs

00 mg tid 500 0.34 130 Multiple sustained episodes of TdP

tes; tid ¼ 3 times a day; Tp-e/QT ratio ¼ ratio between the interval from the peak to the end of the T-wave and

FIGURE 1 Mexiletine’s Impact on TWA

Effect of mexiletine on long QT-induced macro T-wave alternans (TWA): Electrocardiogram strips showing macrovolt TWA (A) and its resolution after the first dose of

mexiletine (B).

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Mexiletine exhibited no significant effect on QRSduration (105.1 � 9 ms in pre-mexiletine vs. 105 � 5.9ms in post-mexiletine findings, p ¼ 0.9).

EFFECTS OF MEXILETINE ON QT-RR SLOPES. TdP isoften initiated after a characteristic short-long-shortventricular cycle sequence. As shown in Figure 3A,QT and Tp-e intervals were disproportionally pro-longed after a longer RR interval (pause) that man-ifested as a larger T-wave with an increased Tp-e

interval and facilitated the development of a R-on-Tectopic beat capable of initiating TdP. Mexiletineblunted the change in the T-wave amplitude and Tp-e

duration after the pause (Figure 3B).The QT-RR slopes were generated by plotting 112

pre-mexiletine QT-RR pairs and 118 post-mexiletineQT-RR pairs in 8 patients for whom detailed telem-etry tracings were available. In all 8 patients, mex-iletine treatment led to significant blunting of QT-RRrelationship slopes (Figures 3C and 3D).

DISCUSSION

Our results suggest thatmexiletinemay be an effectivetreatment for acute termination of TdP in several ac-quired causes of QT interval prolongation. Mexiletineshortened the QTc and Tp-e interval and abolishedTWA. Additionally, it decreased the Tp-e/QT ratioand blunted the bradycardia-dependent prolonga-tion of the QT and Tp-e interval to account forits antiarrhythmic efficacy. The proposed ionic

mechanism of this antiarrhythmic property is blockadeof INa-L current.

Delayed ventricular repolarization facilitatesL-type calcium current (ICa-L) reactivation that leadsto the development of early afterdepolarization (EAD)during action potential phases 2 and 3. This serves asthe trigger for TdP (23,24). Factors decreasing the netrepolarizing force can amplify intrinsic dispersion ofventricular repolarization as a result of preferentialprolongation of the action potential in cells withbaseline weak repolarization forces such as mid-myocardial M cells (25). Amplified dispersion of ven-tricular repolarization manifests an increased Tp-e

and Tp-e/QT ratio on the ECG and serves as are-entrant substrate for the development of TdP. QTprolongation is associated with an enhanced QT-RRrelationship through enhancement of INa-L (12). Inother words, the QT and Tp-e intervals are prolongedmore significantly during bradycardia or after apause. In the presence of QT-prolonging agents, theenhanced QT-RR relationship is termed reverse-usedependence (14,26). This can explain why TdP isoften bradycardia or pause dependent.

INa-L is a small portion of the sodium current thatexhibits a slow inactivation kinetic and remainsactive mainly during the action potential plateauphase. Pathophysiologically, an increase in INa-L

contributes to the arrhythmogenic milieu facilitatingthe development of TdP by the following mecha-nisms: 1) an increase in dispersion of repolarization inresponse to preferential prolongation in cells with

FIGURE 2 Effect of Mexiletine on QT Interval and TdP

Electrocardiogram (ECG) strips of 4 cases displaying long QT pre-mexiletine, followed by torsade de pointes (TdP), and post-mexiletine ECG strips. In case A,

the post-mexiletine ECG was recorded 24 h after the first dose and after a total of 400 mg. In case B, it was recorded 15 h after the first dose and after a total of 300 mg.

In case C, the post-mexiletine ECG was recorded 25 h after the first dose and after 600 mg of mexiletine. In case D, the post-mexiletine ECG was recorded 23 h after the

first dose and after a total of 600 mg. Note that all 4 episodes of TdP occurred following a long-short interval.

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weak repolarization reserve such as M cells (27);2) facilitation of the development of EADs (28,29);and 3) enhancement of the QT-RR relationship (12,14).Antiarrhythmic effects of INa-L blockade have beenpreviously documented in animal experiments(28,30–32). Using canine left ventricular wedge prep-aration, Shimizu and Antzelevitch showed that inwedge models of LQTS1, LQTS2 (31), and LQTS3(28,31), INa-L blockade by mexiletine was effective inabbreviating repolarization, decreasing dispersion ofrepolarization, suppressing EADs, and preventingTdP. Similarly, in canine models of chronic atrioven-tricular block, the INa-L blocker ranolazine effectivelyprevented induction of TdP by dofetilide (33). Werecently showed that in a rabbit left ventricularwedge model of Timothy syndrome (ICa.L augmenta-tion by BayK 8644), INa-L blockade by mexiletineconferred similar antiarrhythmic effects (15).

On the clinical side, use of oral mexiletine or rano-lazine (a potent INa-L blocker) was largely limited topatients with genotype-confirmed LQTS3 who had again of function mutation in INa-L (20,34). Our current

study expands that observation to the use of mex-iletine in acquired LQTS resulting from different cau-ses. It validates pre-clinical data that INa-L is amplifiedin QT prolongation regardless of the underlying cau-ses, plays a central role in rate dependence of the QTinterval, and is vital in the pathogenesis of TdP. Theinhibitory effect of mexiletine on TdP in our presentstudy occurred likely through inhibition of INa-L

because it shortened the QT and Tp-e intervals (2important ECG repolarization parameters) withoutsignificantly changing the QRS duration (an index ofdepolarization). As shown in our study, the etiology ofand predisposition to QT prolongation/TdP in our pa-tient group is diverse and sometimes multifactorial,including stress-induced cardiomyopathy, severe hy-pothyroidism, and the use of cardiac and noncardiacdrugs that prolong the QT interval.

More importantly, an enhanced INa-L appearsto contribute to bradycardia and pause-dependentexaggeration of the QT and Tp-e intervals in diverseclinical situations. This concept is supported bythe finding that mexiletine blunted the QT-RR

FIGURE 3 Effect of Mexiletine on Pause-Dependent QT Prolongation and QT-RR Slope

Pause-dependent QT exacerbation with large T-waves before the use of mexiletine (A) and its resolution after mexiletine (B). (C) Plots displaying the change in QT

intervals across different RR intervals in 8 patients, before (solid circles) and after (open triangles) mexiletine. (D) Bar chart illustration of the change in mean QT-RR

slopes of 8 patients before and after mexiletine use.

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relationship in the patients presented in this series(Figures 3C and 3D) and was uniformly effective intreating TWA and TdP. It should be emphasized thatthe QTc intervals still remained prolonged after thefirst dose of mexiletine, although these intervals wereshortened. This finding indicates that the offendingcauses of QT prolongation were not completely cor-rected when mexiletine terminated TdP. It is knownthat it may take several weeks for QT prolongation instress-induced cardiomyopathy to normalize (35).This further indicates that blockade of INa-L may be apotentially promising treatment for congenital LQTSin which the underlying causes cannot be removed.It also suggests that such a treatment with blockadeof INa-L can be used in congenital LQTS that is notnecessarily limited to LQT3 from a gain of functionin INa-L. This suggestion is supported by a recentstudy showing that mexiletine is useful in thetreatment of LQT8, in which the underlying mecha-nism is a gain of the function in L-type calciumcurrent (15).

Ranolazine is also an INa-L blocker that has beenshown to suppress TdP in animal experiments (33).The major reason that we chose mexiletine instead ofranolazine is that ranolazine also blocks IKr (36) andcan prolong the QT interval in patients (37). Addi-tionally, ranolazine was linked to QT prolongationand TdP in a recent case report (38). Lidocaine,another Class Ib agent that also blocks late INa-L (39),shortens the QT interval, and in a some cases it wasshown to be effective in treatment of long QT andTdP (40,41). However, mexiletine inhibits INa-L moreselectively than does lidocaine. IC50 of mexiletine forINa-L is 17.6 mmol/l, which is close to its therapeuticplasma concentration (15), whereas IC50 of lidocaineis 89 mmol/l (39), significantly higher than its thera-peutic plasma concentration (42). However, it wouldbe important to compare the efficacy of lidocainewith that of mexiletine in future clinical studiesbecause the intravenous administration route oflidocaine would be advantageous in critically illpatients.

PERSPECTIVES

COMPETENCY IN MEDICAL KNOWLEDGE: Mexiletine, an

INa-L blocker, may be useful to reverse the cellular mechanism of

acquired LQT and TdP. In patients with acquired LQT and TdP

refractory to conventional measures, clinicians may consider the

use of mexiletine.

TRANSLATIONAL OUTLOOK: This study should prompt

future examination of the role of mexiletine in acquired LQT and

TdP in a larger prospective fashion.

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STUDY LIMITATIONS. First, this study lacks acomparative treatment arm. However, all patientsreceived conventional emergency treatment of longQT/TdP, and mexiletine was used only when con-ventional measures failed to resolve the arrhythmo-genic abnormalities.

Second, it may be argued that where a reversiblecause was identified, it was the withdrawal ofoffending agent and not initiation of therapy withmexiletine that led to the beneficial clinical endpoint.However, the antiarrhythmic effects were consis-tently seen shortly (within 2 h) after the first doseof mexiletine in cases where TdP was refractory toconventional treatment and well earlier than the timewhen withdrawal of offending agent would havebeen extant. In fact, there were 4 cases in whichfrequent episodes of TdP persisted for more than24 h despite conventional therapy combined withintravenous isoproterenol infusion or transvenoustemporary cardiac pacing. As in the other 8 cases,mexiletine terminated TdP within 2 h after initiationof mexiletine.

Third, although these findings support the use ofmexiletine in acquired LQTS, the duration of treat-ment optimal for this therapeutic benefit remainsunclear. In 1 patient of this series, TdP resolved andthe QT interval normalized with mexiletine, whichwas discontinued 6 days after treatment started. TheQT interval then lengthened, and TdP recurred. Thiscondition resolved when mexiletine was restarted.

Further studies to elucidate the duration of therapywill need to be performed.

CONCLUSIONS

With reversal of the offending cause, electrolytereplacement, and watchful waiting, TdP resolves inthe majority of cases. However, in cases refractory tothose treatments, an additional therapeutic optionmay be mexiletine. Proof of this concept will requirestudies of considerably larger size and scope.

REPRINT REQUESTS AND CORRESPONDENCE: Dr.Gan-Xin Yan, Lankenau Medical Center and Lanke-nau Institute of Medical Research, 100 LancasterAvenue, Wynnewood, Pennsylvania 19096. E-mail:yanganxin@comcast.net.

RE F E RENCE S

1. Dessertenne F. Ventricular tachycardia with 2variable opposing foci. Arch Mal Coeur Vaiss 1966;59:263–72.

2. Schwartz PJ, Malliani A. Electrical alternation ofthe T-wave: clinical and experimental evidence ofits relationship with the sympathetic nervoussystem and with the long Q-T syndrome. Am HeartJ 1975;89:45–50.

3. Roden DM. Taking the “idio” out of “idiosyn-cratic”: predicting torsades de pointes. Pacing ClinElectrophysiol 1998;21:1029–34.

4. Halkin A, Roth A, Lurie I, Fish R, Belhassen B,Viskin S. Pause-dependent torsade de pointesfollowing acute myocardial infarction: a variant ofthe acquired long QT syndrome. J Am Coll Cardiol2001;38:1168–74.

5. YamadaY, Tani T,HommaM,Saito S. Twocases oftorsades de pointes associated with takotsubo car-diomyopathy as the second insult. J Electrocardiol2011;44:806–9.

6. Methe H, Hinterseer M, Wilbert-Lampen U,Beckmann BM, Steinbeck G, Kääb S. Torsades depointes: a rare complication of an extra-adrenalpheochromocytoma. Hypertens Res 2007;30:1263–6.

7. Danenberg HD, Hasin Y. Polymorphic ventricu-lar tachycardia and repolarization abnormalitiesaccompanying intracerebral hemorrhage. Circula-tion 2000;101:E81.

8. Banai S, Tzivoni D. Drug therapy for torsade depointes. J Cardiovasc Electrophysiol 1993;4:206–10.

9. Roden DM. A practical approach to torsade depointes. Clin Cardiol 1997;20:285–90.

10. Kay GN, Plumb VJ, Arciniegas JG,Henthorn RW, Waldo AL. Torsade de pointes: thelong-short initiating sequence and other clinicalfeatures: observations in 32 patients. J Am CollCardiol 1983;2:806–17.

11. Locati EH, Maison-Blanche P, Dejode P,Cauchemez B, Coumel P. Spontaneous sequencesof onset of torsade de pointes in patients withacquired prolonged repolarization: quantitativeanalysis of Holter recordings. J Am Coll Cardiol1995;25:1564–75.

12. Guo D, Lian J, Liu T, et al. Contribution of latesodium current (I(Na-L)) to rate adaptation ofventricular repolarization and reverse use-dependence of QT-prolonging agents. HeartRhythm 2011;8:762–9.

13. Belardinelli L, Giles WR, Rajamani S,Karagueuzian HS, Shryock JC. Cardiac late Na�

current: proarrhythmic effects, roles in long QTsyndromes, and pathological relationship toCaMKIIand oxidative stress. Heart Rhythm 2015;12:440–8.

14. Jia S, Lian J, Guo D, et al. Modulation of thelate sodium current by ATX-II and ranolazine af-fects the reverse use-dependence and proar-rhythmic liability of IKr blockade. Br J Pharmacol2011;164:308–16.

15. Gao Y, Xue X, Hu D, et al. Inhibition of latesodium current by mexiletine: a novel pharmo-therapeutical approach in timothy syndrome. CircArrhythm Electrophysiol 2013;6:614–22.

16. Bennett PB, Yazawa K, Makita N, George AL Jr.Molecular mechanism for an inherited cardiacarrhythmia. Nature 1995;376:683–5.

17. Takahara A, Sugiyama A, Satoh Y, Hashimoto K.Effects of mexiletine on the canine model ofsparfloxacin-induced long QT syndrome. Eur JPharmacol 2003;476:115–22.

18. Satoh Y, Sugiyama A, Tamura K, Hashimoto K.Effects of mexiletine on the canine cardiovascularsystem complicating cisapride overdose: potentialutility of mexiletine for the treatment of

Badri et al. J A C C : C L I N I C A L E L E C T R O P H Y S I O L O G Y V O L . 1 , N O . 4 , 2 0 1 5

Mexiletine in Acquired Long QT Syndrome A U G U S T 2 0 1 5 : 3 1 5 – 2 2

322

drug-induced long QT syndrome. Jpn J Pharmacol2000;83:327–34.

19. Chézalviel-Guilbert F, Davy JM, Poirier JM,Weissenburger J. Mexiletine antagonizes effects ofsotalol on QT interval duration and its proar-rhythmic effects in a canine model of torsade depointes. J Am Coll Cardiol 1995;26:787–92.

20. Schwartz PJ, Priori SG, Locati EH, et al. LongQT syndrome patients with mutations of theSCN5A and HERG genes have differential re-sponses to Na� channel blockade and to increasesin heart rate: implications for gene-specific ther-apy. Circulation 1995;92:3381–6.

21. Priori SG, Wilde AA, Horie M, et al. HRS/EHRA/APHRS expert consensus statement on the diag-nosis and management of patients with inheritedprimary arrhythmia syndromes: documentendorsed by HRS, EHRA, and APHRS in May 2013and by ACCF, AHA, PACES, and AEPC in June 2013.Heart Rhythm 2013;10:1932–63.

22. Woosley RL, Wang T, Stone W, et al. Pharma-cology, electrophysiology, and pharmacokineticsof mexiletine. Am Heart J 1984;107:1058–65.

23. Guo D, Zhou J, Zhao X, et al. L-type calciumcurrent recovery versus ventricular repolarization:preserved membrane-stabilizing mechanism fordifferent QT intervals across species. Heart Rhy-thm 2008;5:271–9.

24. Wu Y, Carlsson L, Liu T, Kowey PR, Yan G-X.Assessment of the proarrhythmic potential ofthe novel antiarrhythmic agent AZD7009 anddofetilide in experimental models of torsadesde pointes. J Cardiovasc Electrophysiol 2005;16:898–904.

25. Antzelevitch C. Role of transmural dispersionof repolarization in the genesis of drug-inducedtorsades de pointes. Heart Rhythm 2005;2:S9–15.

26. Roden DM. Drug-induced prolongation of theQT interval. N Engl J Med 2004;350:1013–22.

27. Sicouri S, Antzelevitch C. A subpopulation ofcells with unique electrophysiological propertiesin the deep subepicardium of the canine ventricle:the M cell. Circ Res 1991;68:1729–41.

28. Shimizu W, Antzelevitch C. Cellular basis forthe ECG features of the LQT1 form of the long-QTsyndrome: effects of beta-adrenergic agonists andantagonists and sodium channel blockers ontransmural dispersion of repolarization andtorsade de pointes. Circulation 1998;98:2314–22.

29. Guo D, Zhao X, Wu Y, Liu T, Kowey PR, Yan G-X. L-type calcium current reactivation contributesto arrhythmogenesis associated with action po-tential triangulation. J Cardiovasc Electrophysiol2007;18:196–203.

30. Antzelevitch C, Belardinelli L. The role of so-dium channel current in modulating transmuraldispersion of repolarization and arrhythmogenesis.J Cardiovasc Electrophysiol 2006;17 Suppl 1:S79–85.

31. Shimizu W, Antzelevitch C. Sodium channelblock with mexiletine is effective in reducingdispersion of repolarization and preventing torsadedes pointes in LQT2 and LQT3 models of the long-QT syndrome. Circulation 1997;96:2038–47.

32. Sicouri S, Timothy KW, Zygmunt AC, et al.Cellular basis for the electrocardiographic andarrhythmic manifestations of Timothy syndrome:effects of ranolazine. Heart Rhythm 2007;4:638–47.

33. Antoons G, Oros A, Beekman JDM, et al. LateNa(þ) current inhibition by ranolazine reducestorsades de pointes in the chronic atrioventricularblock dogmodel. J AmColl Cardiol 2010;55:801–9.

34. Moss AJ, Zareba W, Schwarz KQ, Rosero S,McNitt S, Robinson JL. Ranolazine shortens repo-larization in patients with sustained inward sodiumcurrent due to type-3 long-QT syndrome.J Cardiovasc Electrophysiol 2008;19:1289–93.

35. Matsuoka K, Okubo S, Fujii E, et al. Evaluationof the arrhythmogenicity of stress-induced“takotsubo cardiomyopathy” from the timecourse of the 12-lead surface electrocardiogram.Am J Cardiol 2003;92:230–3.

36. Antzelevitch C, Belardinelli L, Zygmunt AC,et al. Electrophysiological effects of ranolazine, anovel antianginal agent with antiarrhythmicproperties. Circulation 2004;110:904–10.

37. Chaitman BR, Skettino SL, Parker JO, et al.Anti-ischemic effects and long-term survival dur-ing ranolazine monotherapy in patients withchronic severe angina. J Am Coll Cardiol 2004;43:1375–82.

38. Liu Z, Williams RB, Rosen BD. The potentialcontribution of ranolazine to torsade de pointe.J Cardiovasc Dis Res 2013;4:187–90.

39. Dumaine R, Kirsch GE. Mechanism of lidocaineblock of late current in long Q-T mutant Na�

channels. Am J Physiol 1998;274:H477–87.

40. Bansal AM, Kugler JD, Pinsky WW,Norberg WJ, Frank WE. Torsade de pointes:successful acute control by lidocaine andchronic control by tocainide in two patients—one each with acquired long QT and thecongenital long QT syndrome. Am Heart J 1986;112:618–21.

41. Assimes TL, Malcolm I. Torsade de pointeswith sotalol overdose treated successfully withlidocaine. Can J Cardiol 1998;14:753–6.

42. McEvoy G. Lidocaine hydrochloride. In:American Hospital Formulary Service: Drug Infor-mation 95. Bethesda, MD: American Society ofHealth-System Pharmacists, 1995:1102–5.

KEY WORDS late sodium current, long QT,mexiletine, torsades de pointes