The proarrhythmic effect of cardiac resynchronization ...repositorio.chlc.min-saude.pt/bitstream/10400.17/2040/1/RPC 2014... · Rev Port Cardiol. 2014;33(5) ... The proarrhythmic

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Rev Port Cardiol. 2014;33(5):309.e1---309.e7

Revista Portuguesa de

CardiologiaPortuguese Journal of Cardiology

www.revportcardiol.org

CASE REPORT

The proarrhythmic effect of cardiac resynchronizationtherapy: An issue that should be borne in mind�

Nuno Cabanelasa,∗, Mário Oliveirab, Manuel Nogueira da Silvab, Pedro Cunhab,Bruno Valenteb, Ana Lousinhab, Sofia Santosb, Luísa Brancob, Rui Ferreirab

a Servico de Cardiologia, Hospital de Santarém, Santarém, Portugalb Servico de Cardiologia, Hospital Santa Marta, Centro Hospitalar de Lisboa Central, Lisboa, Portugal

Received 14 December 2012; accepted 20 January 2014Available online 18 June 2014

KEYWORDSCardiacresynchronization;Epicardial pacing;Repolarizationheterogeneity

Abstract The demonstrated benefits of cardiac resynchronization therapy (CRT) in reducingmortality and hospitalizations for heart failure, improving NYHA functional class and inducingreverse remodeling have led to its increasing use in clinical practice. However, its potentialcontribution to complex ventricular arrhythmias is controversial.

We present the case of a female patient with valvular heart failure and severe systolic dys-function, in NYHA class III and under optimal medical therapy, without previous documentedventricular arrhythmias. After implantation of a CRT defibrillator, she suffered an arrhythmicstorm with multiple episodes of monomorphic ventricular tachycardia (VT), requiring 12 shocks.Subsequently, a pattern of ventricular bigeminy was observed, as well as reproducible VT runsinduced by biventricular pacing.

Since no other vein of the coronary sinus system was accessible, it was decided to implantan epicardial lead to stimulate the left ventricle, positioned in the left ventricular mid-lateralwall. No arrhythmias were detected in the following six months.

This case highlights the possible proarrhythmic effect of biventricular pacing with a leftventricular lead positioned in the coronary sinus venous system.© 2012 Sociedade Portuguesa de Cardiologia. Published by Elsevier España, S.L. All rightsreserved.

PALAVRAS-CHAVERessincronizacãocardíaca;Pacing epicárdico;

Terapêutica de ressincronizacão cardíaca e efeito pró-arrítmico: um problema quedeve ser lembrado

Resumo Os benefícios demonstrados com a terapêutica de ressincronizacão cardíaca (TRC)na reducão da mortalidade e hospitalizacão por ICC, melhoria da classe funcional e obtencão

� Please cite this article as: Cabanelas N, Oliveira M, Nogueira da Silva M, et al. Terapêutica de ressincronizacão cardíaca e efeitopró-arrítmico: um problema que deve ser lembrado. Rev Port Cardiol. 2014;33:309.e1---309.e7.

∗ Corresponding author.E-mail address: [email protected] (N. Cabanelas).

2174-2049/© 2012 Sociedade Portuguesa de Cardiologia. Published by Elsevier España, S.L. All rights reserved.

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309.e2 N. Cabanelas et al.

Heterogeneidade darepolarizacão

de remodelagem inversa em doentes selecionados com insuficiência cardíaca (ICC), têm con-tribuído para a crescente utilizacão destes dispositivos na prática clínica.

No entanto, permanece controverso o impacto da TRC como fator causador de arritmiasventriculares complexas. Apresentamos o caso duma doente com cardiopatia valvular oper-ada, disfuncão sistólica grave e ICC classe III da NYHA, com terapêutica médica otimizada,sem documentacão prévia de arritmias ventriculares significativas. Após implantacão do sis-tema de TRC com cardioversor-desfibrilhador, desenvolveu quadro de tempestade arrítmica commúltiplos episódios de taquicardia ventricular monomórfica (TV) e necessidade de 12 choques,mantendo padrão de bigeminismo ventricular reprodutível e inducão de salvas de TV pelo pac-ing biventricular. Dada a inacessibilidade a outra veia tributária do seio coronário foi decididoimplantar elétrodo epicárdico em localizacão diferente (de veia póstero-lateral para posicãolateral-mediana), sem registo de recorrência de arritmias num follow-up de seis meses. Estecaso sugere que a TRC pode contribuir para um efeito pró-arrítmico com consequências clínicaspotencialmente graves.© 2012 Sociedade Portuguesa de Cardiologia. Publicado por Elsevier España, S.L. Todos osdireitos reservados.

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he benefits of cardiac resynchronization therapy (CRT) ineducing mortality and hospitalizations for heart failureHF), improving NYHA functional class and inducing reverseemodeling have been amply demonstrated in various mul-icenter trials in the last 10 years, leading to a considerablexpansion of indications for biventricular (BiV) pacing.1---8

CRT can have adverse effects, most of which are relatedo procedural complications, infection and system malfunc-ion. In recent years there has also been debate concerninghe possible contribution of BiV pacing to the occurrence ofomplex ventricular arrhythmias.

ase report

58-year-old female patient with controlled mild hyperten-ion, type 2 diabetes and dyslipidemia was being followed inhe cardiology outpatient clinic for valvular HF and perma-ent atrial fibrillation (AF). She had previously undergoneitral valve replacement with a mechanical valve due to

evere mitral stenosis.During follow-up, progressive clinical deterioration was

een to NYHA class III under optimal medical therapyOMT). The ECG showed QRS interval of 150 ms and com-lete left bundle branch block. She had no history ofentricular arrhythmias during follow-up. Serial echocardio-rams showed steadily worsening global systolic function,jection fraction (EF) falling from 24% to 13%. Six yearsfter valve replacement surgery, she had severely impairedlobal systolic function, with left ventricular (LV) end-iastolic diameter of 82 mm, EF estimated at 13% by theodified Simpson’s rule, and echocardiographic criteria of

ntraventricular dyssynchrony, with tissue synchronizationmaging showing septal-lateral delay of 100 ms, two-

imensional strain imaging showing radial strain of 448 msith inferior-anteroseptal delay but no ventricular dyssyn-hrony (pulmonary and aortic pre-ejection times of 78 msnd 105 ms, respectively). Right ventricular (RV) function

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igure 1 Angiogram of the coronary sinus, showing sparseenous system.

as also impaired, with tricuspid annular plane systolicxcursion of 5 mm.

A VVIR mode CRT defibrillator (CRT-D) was implanted withhe LV lead positioned in a posterolateral vein (Figure 1)ith a different ostium from that of the coronary sinus, theenous system of which was sparse, consisting of small andarkedly angulated vessels (Figure 2). In our center, theosterolateral vein is often used when the branches of theoronary sinus are technically difficult to access, althought is generally difficult to characterize. However, this veins only used as an alternative, since the distance betweent and the RV apex gives insufficient time for myocardial

ctivation. Furthermore, the fact that both leads activatinghe ventricular mass are relatively close could trigger newyssynchrony by the late activation of more distant areas ofhe myocardium.

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The proarrhythmic effect of cardiac resynchronization therapy:

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One month after implantation, the patient returnedto our department after suffering 12 shocks in 24 hours.Device interrogation revealed these to have been appropri-ate shocks in response to an arrhythmic storm of multipleepisodes of rapid ventricular tachycardia (VT) with a meancycle length of 250 ms (Figure 3). At the same time repro-ducible ventricular bigeminy and VT runs induced by BiVpacing were seen. Various programming modes were tested

with different pulse polarities, amplitudes and widths, aswell as left ventricular pacing alone, none of which elimi-nated the ventricular extrasystoles. In view of the failureof these attempts, pacing via the left ventricular lead

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An issue that should be borne in mind 309.e3

as switched off and the patient regained natural rhythmithout ventricular extrasystoles, with RV pacing set to ainimum of 40 bpm. The CRT-D was programmed with three

ones: VT-1, from 171 bpm with two bursts of antitachycar-ia pacing; VT-2, from 182 bpm, with two ramps followed ifecessary by a 40-J shock; and VF, from 200 bpm, with upo six 40-J shocks.

Holter 24-hour monitoring performed two months laterhowed natural rhythm (AF) in 99% of the record, with only95 isolated dimorphic ventricular extrasystoles, one pairnd one 4-complex run. The patient was under medicationith amiodarone 200 mg/day and carvedilol 6.25 mg twiceaily.

Echocardiography five months after switching off LV pac-ng showed continuing very low EF (13%) with evidencef intra- and interventricular dyssynchrony; the patientemained in NYHA class III.

It was decided to make another attempt to implementRT. Since no other branch of the coronary sinus could beatheterized, an epicardial lead was implanted in the lateralV wall (Figure 4). The alternative of repositioning the RVead to a septal position was not chosen because, beforeRT implantation, the segments with the latest activationere those of the lateral wall, the distance between the

eads would not be significantly increased by this change,nd in order to begin pacing via the LV lead it would have toe implanted in a less arrhythmogenic position.

An epicardial lead was implanted between the secondnd third obtuse marginals by submammary thoracotomy.

One month later, the patient was still in NYHA class III,ith poor global systolic function. The LV pacing percentage

as 89% and the RV pacing percentage was 13%. The lowercentage of BiV pacing is explained by the rapid intrinsicates resulting from the patient’s AF. However, no ventricu-ar arrhythmias were recorded by the device.

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Figure 4 Chest X-ray, anteroposterior view, showing pacingll

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ead in the posterior vein (blue arrow) and epicardial lead inateral position (red arrow).

Digoxin was added to the patient’s therapeutic regimeo control her intrinsic ventricular rate, the minimum pac-ng rate was raised to 80 bpm, and she was enrolled in aardiac rehabilitation program. We opted for a conservativepproach to maximize BiV pacing rate through optimizingedical therapy and reprogramming the device, given the

heoretically greater risk of loss of capture by the epicardialead than if the lead had been positioned in the coronaryinus venous system. If this strategy failed, the next stepould be ablation of the atrioventricular node. If the LV

ead had been in the coronary venous system, then nodalblation would have been the first option.

At six months after implantation of the epicardial LV leadnd after an increase in the percentage of BiV pacing, theatient was still in NYHA class III, but reported slight symp-omatic improvement in her day-to-day activities, and herF had risen to 19%. No new episodes of decompensated HFccurred and no ventricular arrhythmias were detected byemote monitoring during this period.

iscussion

nitial reports of the impact of CRT on the incidence ofentricular arrhythmias show an antiarrhythmic effect,9,10

hich could be due to reduction of wall stress caused byhe inverse remodeling induced by BiV pacing, decreasedispersion of ventricular repolarization resulting from dualepolarization wave fronts,11,12 and reduced sympatheticervous system activation.13

Other studies suggested that this antiarrhythmic effects due to reductions in the number of ventricularxtrasystoles,14 the incidence of tachyarrhythmic events15

nd the inducibility of sustained VT.16 More recent research

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N. Cabanelas et al.

as indicated that this effect is mainly seen in patientsho respond to CRT, as a consequence of the hemodynamic

mprovement induced by BiV pacing,17,18 but not in non-esponders.

Indications for CRT have widened in the last 10 years andesearch into its consequences has intensified, but its elec-rophysiological effects on the incidence of sudden deathnd ventricular arrhythmias are still poorly understood.

Cases have been reported of increased arrhythmic eventsn some patients when treated with BiV pacing.19---21 In005, Shukla et al.19 described a series of 145 consecutiveatients, five of whom developed arrhythmic storm aftermplantation of a CRT-D, which was permanently resolvedy discontinuing LV pacing. Similarly, Medina-Ravell et al.20

ssessed 29 patients who received a CRT-D, four of whomeveloped ventricular extrasystoles with BiV pacing, elimi-ated when LV pacing was ended. The same phenomenon iseen in the case presented here.

Further evidence is found in the two largest randomizedlinical trials to assess the effects of CRT in patients with andithout an implantable defibrillator, which showed a reduc-

ion in all-cause mortality compared to OMT (COMPANION4

nd CARE-HF5), the percentage of sudden death as a causef death was slightly higher in those without a defibrillator.22

In the COMPANION trial, there was a statistically sig-ificant reduction of 36% in all-cause death (p=0.003) inatients under OMT and CRT compared to OMT only. How-ver, the incidence of sudden death was higher in thosender CRT with pacing only plus OMT than in those with OMTnly (7.8% vs. 5.8%), while in those with CRT-D and OMTt was only 2.9%. Analysis of causes of death in the threeroups shows that sudden death was responsible in 36.6%f patients with CRT with pacing only plus OMT, 23.4% ofhose with OMT only, and only 16.2% of those with CRT-D andMT.22

In the CARE-HF trial, although mortality was lower inatients undergoing CRT than in those receiving OMT only,he percentage of the former suffering sudden death wasigher (35.4% vs. 31.7%).

However, evidence to the contrary recently came fromhe REVERSE study, which assessed the incidence ofT/ventricular fibrillation and sustained VT in patients withRT-D devices, one group with BiV pacing on and the otherith pacing off. After two years of follow-up, the incidencef arrhythmic events was similar in the two groups (18.7%s. 21.9%, p=0.84).23

In the normal sequence of myocardial activation, thendocardium is depolarized before the more epicardial lay-rs, while repolarization travels in the opposite directionfrom epicardium to endocardium). BiV pacing is normallyffected via an endocardial lead placed in the RV and aead placed inside the coronary sinus or one of its branches,nd so the LV myocardium is stimulated via the epicardium.picardial pacing involves a non-physiological activationequence in which the vector of the transmural propagations reversed, resulting in delayed endocardial depolarizationnd earlier epicardial depolarization.24 Experimental stud-es have shown that epicardial-endocardial conduction time

s significantly longer than endocardial-epicardial conduc-ion time, due to a zone of myocardial wall between theeep subendocardium and mid-myocardial layers.25,26 Theesulting increased dispersion of repolarization prolongs QT

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and JT intervals and the interval between the peak and theend of the T wave.25,27

Furthermore, a small number of predisposed patientsmay be more likely to suffer reentrant phenomena. Thepresence of cardiomyopathy, use of QT-prolonging drugs,and autonomic dysregulation can also promote thesephenomena.28,29

Identification of factors that predispose to ventriculararrhythmias caused by BiV pacing is thus of considerableclinical importance in the assessment of candidates for thistherapy and in the decision whether to implant a CRT-Dsystem.

The predictors of arrhythmias in these patients have notbeen fully identified. In a study of 75 patients undergoingCRT, variation in QT dispersion before and after implantationwas an independent predictor of major arrhythmic events;in a follow-up of 807 days, in the group with increased QTdispersion the incidence of events was 29%, while in thosein whom it decreased, the incidence was 3% (p=0.0017).30

The same study30 assessed the interval between the peakand the end of the T wave (Tpeak-end), another marker of dis-persion of repolarization. Patients who suffered arrhythmicevents during follow-up had a significantly smaller reductionin Tpeak-end than those who were event-free (−1.5±12.8 msvs. −20.0±5.4 ms, p=0.047).

The mechanisms involved in this differing QT dispersionresponse to CRT have not been investigated. It is thoughtthat factors such as severe systolic dysfunction,29 perfusiondisturbances31 and stimulation of LV myocardium in areasclose to fibrotic tissue32 could in theory be related tochanges in QT dispersion.

Dilated cardiomyopathy is associated with ventricu-lar fibrosis, changes in muscle tissue architecture andabnormalities of cellular ultrastructure, particularly in cellmembranes.33,34 The electrophysiological properties of car-diomyopathic myocardium are also altered by lines ofconduction block resulting from fibrosis and areas of abnor-mal conductibility and refractoriness.35 The zones withaltered electrophysiological properties are not homoge-nous throughout the dysfunctional myocardium,36 and thepatterns of their distribution appear to differ betweenischemic and non-ischemic dilated cardiomyopathy,36 withmore diffuse involvement, mainly in the basal segments,in the latter compared to the former, in which thesezones tend to be restricted to particular arterial territoriesand typically affect the endocardium more extensively.37,38

In the case presented, the patient had severe valvu-lar disease and had undergone mitral valve replacement,which may have altered the tissue architecture and hencethe distribution of zones with altered electrophysiologicalproperties.

When a pro-arrhythmic effect of BiV pacing is suspected,an alternative site for LV stimulation can reduce arrhythmo-genicity. In our patient, the lack of options led us to adopt asurgical approach, and during thoracotomy threshold testswere performed in different parts of the epicardium andthe induction of ventricular extrasystoles by BiV pacing wasassessed.

Various strategies have been tried to overcome thepotential arrhythmic risk of LV stimulation via branches ofthe coronary sinus, including endocardial LV pacing with thelead positioned via transseptal puncture. Initial results of

An issue that should be borne in mind 309.e5

his procedure, still in the early stages of evaluation, areromising.39,40

Assessment of heterogeneity of repolarization duringmplantation is considered of little value, since no cor-elation has been established between changes in thesearameters and adverse events, and any pro-arrhythmicffect may only be manifested hours or days aftermplantation.41

onclusion

RT is not without adverse effects. Although its benefitslearly outweigh the risks in patients with indication forhis therapy, in rare cases BiV pacing may induce arrhyth-ias. Reversal of the physiological depolarization sequence

ncreases dispersion of repolarization, promoting reentryhenomena and increasing the incidence of ventricularrrhythmias in some patients.

Although the paradoxical increase in arrhythmogenicityith CRT is uncommon, it can have serious clinical conse-uences that reprogramming alone cannot prevent. In thease presented, only removal of the pacing lead from theoronary sinus eliminated the ventricular arrhythmia. Sinceentricular resynchronization was necessary, an alternativeite for the LV pacing lead had to be found, and an epicardialpproach was the one chosen.

thical disclosures

rotection of human and animal subjects. The authorseclare that no experiments were performed on humans ornimals for this study.

onfidentiality of data. The authors declare that they haveollowed the protocols of their work center on the publica-ion of patient data.

ight to privacy and informed consent. The authors havebtained the written informed consent of the patients orubjects mentioned in the article. The corresponding authors in possession of this document.

onflicts of interest

he authors have no conflicts of interest to declare.

eferences

1. Linde C, Leclercq C, Rex S, et al. Long-term benefits of biven-tricular pacing in congestive heart failure: results from theMUltisite STimulation in cardiomyopathy (MUSTIC) study. J AmColl Cardiol. 2002;40:111---8.

2. Abraham W, Fisher W, Smith A, et al., The MIRACLE StudyGroup. Cardiac resynchronization in chronic heart failure, Mul-ticenter Insync Randomized Clinical Evaluation. N Engl J Med.2002;346:1845---53.

3. Abraham W, Young J, Leon A, et al., on behalf of the

Multicenter InSync ICD II (MIRACLE ICD II) Study Group.Effects of cardiac resynchronization on disease progression inpatients with left ventricular systolic dysfunction, an indica-tion for an implantable cardioverter-defibrillator, and mildly

Page 6

3

1

1

1

1

1

1

1

1

1

1

2

2

2

2

2

2

2

2

2

2

3

3

3

3

3

3

3

3

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09.e6

symptomatic chronic heart failure. Circulation. 2004;110:2864---8.

4. Bristow M, Saxon L, Boehmer J, et al., Comparison of MedicalTherapy. Pacing and Defibrillation in Heart Failure (COMPAN-ION) Investigators. Cardiac resynchronization therapy with orwithout an implantable defibrillator in advanced chronic heartfailure. N Engl J Med. 2004;350:2140---50.

5. John G, Cleland M, Daubert J, et al., for the Cardiac Resyn-chronization - Heart Failure (CARE-HF) Study Investigators. Theeffect of cardiac resynchronization on morbidity and mortalityin heart failure. N Engl J Med. 2005;352:1539---49.

6. Linde C, Abraham W, Gold M, et al. Randomized trial of cardiacresynchronization in mildly symptomatic heart failure patientsand in asymptomatic patients with left ventricular dysfunc-tion and previous heart failure symptoms. J Am Coll Cardiol.2008;52:1834---43.

7. Solomon S, Foster E, Bourgoun M, et al., (MADIT-CRT Investiga-tors). Effect of cardiac resynchronization therapy on reverseremodeling and relation to outcome. Multicenter AutomaticDefibrillator Implantation Trial-Cardiac Resynchronization Ther-apy. Circulation. 2010;122:985---92.

8. Tang A, Wells G, Talajic M, et al., Resynchronization-Defibrillation for Ambulatory Heart Failure Trial Investigators.Cardiac resynchronization therapy for mild-to-moderate heartfailure. N Engl J Med. 2010;363:2385---95.

9. Walker S, Levy T, Rex S, et al. Usefulness of suppression of ven-tricular arrhythmia by biventricular pacing in severe congestivecardiac failure. Am J Cardiol. 2000;86:231---3.

0. Zagrodzky J, Ramaswamy K, Page R, et al. Biventricular pac-ing decreases the inducibility of ventricular tachycardia inpatients with ischemic cardiomyopathy. Am J Cardiol. 2001;87:1208---10.

1. Kies P, Bax J, Molhoek S, et al. Effect of left ventricular remod-eling after cardiac resynchronization therapy on frequency ofventricular arrhythmias. Am J Cardiol. 2004;94:130---2.

2. Martinelli Filho M, Pedrosa A, Costa R, et al. Biventricular pacingimproves clinical behavior and reduces prevalence of ventricu-lar arrhythmia in patients with heart failure. Arq Bras Cardiol.2002;78:110---3.

3. Hamdan M, Zagrodzky J, Joglar J, et al. Biventricular pacingdecreases sympathetic activity compared with right ventricularpacing in patients with depressed ejection fraction. Circulation.2000;102:1027---32.

4. Martinelli Filho M, Pedrosa A, Costa R, et al. Biventricular pacingimproves clinical behaviour and reduces prevalence of ventricu-lar arrhythmia in patients with heart failure. Arq Bras Cardiol.2002;78:110---3.

5. Yu C, Bleeker C, Fung J, et al. Left ventricular reverseremodeling, but not clinical improvement predicts long-termsurvival after cardiac resynchronization therapy. Circulation.2005;112:1580---6.

6. Zagrodsky J, Ramaswamy K, Page R, et al. Biventricular pac-ing decreases the inducibility of ventricular tachycardia inpatients with ischemic cardiomyopathy. Am J Cardiol. 2001;87:1208---10.

7. Shahrzad S, Soleiman N, Taban S, et al. The effect ofleft ventricular (LV) remodelling on ventricular arrhythmiain cardiac resynchronization therapy (CRT-D) patients (antiar-rhythmic effect of CRT). Pacing Clin Electrophysiol. 2012;35:592---7.

8. Barsheshet A, Wang P, Moss A, et al. Reverse remodelingand the risk of ventricular tachyarrhythmias in the MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial--- Cardiac Resynchronization Therapy). J Am Coll Cardiol.2011;57:2416---23.

9. Shukla G, Chaudhry G, Orlov M, et al. Potential proarrhyth-mic effect of biventricular pacing: fact or myth? Heart Rhythm.2005;2:951---6.

N. Cabanelas et al.

0. Medina-Ravell V, Lankipalli R, Yan G, et al. Effect of epicar-dial or biventricular pacing to prolong QT interval and increasetransmural dispersion of repolarization: does resynchronizationtherapy pose a risk for patients predisposed to long QT or tor-sade de pointes? Circulation. 2003;107:740---6.

1. Rivero-Ayerza M, Vanderheyden M, Verstreken S, et al.Images in cardiovascular medicine. Polymorphic ventriculartachycardia induced by left ventricular pacing. Circulation.2004;109:2924---5.

2. Carson P, Anand I, O’Connor C, et al. Mode of death in advancedheart failure: the Comparison of Medical, Pacing and Defibril-lation Therapies in Heart Failure (COMPANION) trial. J Am CollCardiol. 2005;46:2329---34.

3. Gold M, Linde C, Abraham W. The impact of cardiac resynchro-nization therapy on the incidence of ventricular arrhythmias inmild heart failure. Heart Rhythm. 2011;8:679---84.

4. Di Diego J, Belardinelli L, Antzelevitch C. Cisapride-inducedtransmural dispersion of repolarization and torsade de pointesin the canine left ventricular wedge preparation during epicar-dial stimulation. Circulation. 2003;108:1027---33.

5. Fish J, Di Diego J, Nesterenko V, et al. Epicardial activation ofleft ventricular wall prolongs QT interval and transmural dis-persion of repolarization: implications for biventricular pacing.Circulation. 2004;109:2136---42.

6. Poelzing S, Dikshteyn M, Rosenbaum D. Transmural conductionis not a two-way street. J Cardiovasc Electrophysiol. 2005;16:455.

7. Bai R, Yang X, Song Y, et al. Impact of left ventricular epi-cardial and biventricular pacing on ventricular repolarizationin normal-heart individuals and patients with congestive heartfailure. Europace. 2006;8:1002---10.

8. Akar F, Rosenbaum D. Transmural electrophysiological hetero-geneities underlying arrhythmogenesis in heart failure. Circ Res.2003;93:638---45.

9. Ray I, Fendelander L, Singh J. Cardiac resynchronizationtherapy and its potential proarrhythmic effect. Clin Cardiol.2007;30:498---502.

0. Chalil S, Yousef Z, Muyhaldeen S, et al. Pacing-induced increasein QT dispersion predicts sudden cardiac death following cardiacresynchronization therapy. J Am Coll Cardiol. 2006;47:2486---92.

1. Bonnemeier M, Wiegand U, Bode F, et al. Impact of infarct-related artery flow on QT dynamicity in patients undergoingdirect percutaneous coronary intervention for acute myocardialinfarction. Circulation. 2003;108:2979---86.

2. Leyva F, Paul F. Is cardiac resynchronisation therapy proarrhyth-mic? Indian Pacing Electrophysiol J. 2008;4:268---80.

3. Unverferth D, Baker P, Swift S, et al. Extent of myocardial fibro-sis and cellular hypertrophy in dilated cardiomyopathy. Am JCardiol. 1986;57:816---20.

4. Sugrue D, Holmes D, Gersh B, et al. Cardiac histologic find-ings in patients with life-threatening ventricular arrhythmiasof unknown origin. J Am Coll Cardiol. 1984;4:952---7.

5. de Bakker J, van Capelle F, Janse M, et al. Fractionated elec-trograms in dilated cardiomyopathy: origin and relation toabnormal conduction. J Am Coll Cardiol. 1996;27:1071---8.

6. Nakahara S, Tung R, Ramirez R, et al. Characterization ofthe arrhythmogenic substrate in ischemic and nonischemiccardiomyopathy: implications for catheter ablation of hemody-namically unstable ventricular tachycardia. J Am Coll Cardiol.2010;55:2355---65.

7. Hsia H, Callans D, Marchlinski F, et al. Characterization ofendocardial electrophysiological substrate in patients withnonischemic cardiomyopathy and monomorphic ventriculartachycardia. Circulation. 2003;108:704---10.

8. Bogun F, Desjardins B, Good E, et al. Delayed-enhanced mag-

netic resonance imaging in nonischemic cardiomyopathy: utilityfor identifying the ventricular arrhythmia substrate. J Am CollCardiol. 2009;53:1138---45.

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39. Whinnett Z, Bordachar P. The risks and benefits of transseptal

endocardial pacing. Curr Opin Cardiol. 2012;27:19---23.

40. Scott P, Yue A, Watts E, et al. Transseptal left ventricular endo-cardial pacing reduces dispersion of ventricular repolarization.Pacing Clin Electrophysiol. 2011;34:1258---66.

An issue that should be borne in mind 309.e7

1. Cazeau S, Leclercq C, Lavegne T, et al. The Multisite Stim-

ulation in Cardiomyopathies (MUSTIC) Study I. Effects ofmultisite biventricular pacing in patients with heart failureand intraventricular conduction delay. N Engl J Med. 2001;344:873---80.