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ESC Guidelines

Guidelines for cardiac pacing and cardiacresynchronization therapy

The Task Force for Cardiac Pacing and Cardiac ResynchronizationTherapy of the European Society of Cardiology. Developed inCollaboration with the European Heart Rhythm Association

Authors/Task Force Members: Panos E. Vardas*(Chairperson) (Greece);Angelo Auricchio (Switzerland); Jean-Jacques Blanc (France); Jean-Claude Daubert (France);Helmut Drexler (Germany); Hugo Ector (Belgium); Maurizio Gasparini (Italy);Cecilia Linde (Sweden); Francisco Bello Morgado (Portugal); Ali Oto (Turkey);Richard Sutton (UK); Maria Trusz-Gluza (Poland)

ESC Committee for Practice Guidelines (CPG): Alec Vahanian (Chairperson) (France), John Camm (UK),Raffaele De Caterina (Italy), Veronica Dean (France), Kenneth Dickstein (Norway), Christian Funck-Brentano

(France), Gerasimos Filippatos (Greece), Irene Hellemans (The Netherlands), Steen Dalby Kristensen (Denmark),Keith McGregor (France), Udo Sechtem (Germany), Sigmund Silber (Germany), Michal Tendera (Poland)Petr Widimsky (Czech Republic), Jose Luis Zamorano (Spain)

Document Reviewers: Silvia G. Priori (Review Coordinator) (Italy), Carina Blomstrom-Lundqvist (Sweden),Michele Brignole (Italy), Josep Brugada Terradellas (Spain), John Camm (UK), Perez Castellano (Spain),John Cleland (UK), Jeronimo Farre (Spain), Martin Fromer (Switzerland), Jean-Yves Le Heuzey (France),

Gregory YH Lip (UK), Jose Luis Merino (Spain), Annibale Sandro Montenero (Italy), Philippe Ritter (France)Martin Jan Schalij (The Netherlands), Christopher Stellbrink (Germany)

Table of Contents

Preamble . . . . . . . . . . . . . . . . . . . . . . . . . . . 2257Introduction . . . . . . . . . . . . . . . . . . . . . . 2258

Pacing in bradyarrhythmia, syncope, and otherspecific conditions . . . . . . . . . . . . . . . . 2258Cardiac resynchronization therapy . . . . . . . 2259

1. Pacing in arrhythmias . . . . . . . . . . . . . . . . 22591.1. Sinus node disease . . . . . . . . . . . . . . . . 2259

1.1.1. Indications for pacing in sinus node disease 2259

1.1.2. Choice of the pacing mode for patientswith sinus node disease . . . . . . . . . . . . 2260

1.2. Atrioventricular and intraventricular

conduction disturbances . . . . . . . . . . . . . 22621.2.1. Indications for pacing . . . . . . . . . . . . . 22621.2.2. Acquired atrioventricular block

in special cases . . . . . . . . . . . . . . . . 2262

1.2.3. Pacing for chronic bifascicular andtrifascicular block . . . . . . . . . . . . . . . 2263

1.2.4. Indications for pacing . . . . . . . . . . . . . 22631.2.5. Choice of pacing mode for patients

with atrioventricular block . . . . . . . . . . 2264

1.3. Recent myocardial infarction . . . . . . . . . . 22651.3.1. Pacing in conduction disturbances related

to acute myocardial infarction . . . . . . . . 2265

1.4. Reflex syncope . . . . . . . . . . . . . . . . . . 22661.4.1. Carotid sinus syndrome . . . . . . . . . . . . 22661.4.2. Vasovagal syncope . . . . . . . . . . . . . . . 2267

1.4.3. Adenosine-sensitive syncope . . . . . . . . . 22681.5. Paediatrics and congenital heart diseases . . . 2269

1.5.1. Sinus node dysfunction and bradycardia

tachycardia syndrome at young ages . . . . 2270

* Corresponding author: Panos Vardas, Department of Cardiology, Heraklion University Hospital, PO Box 1352 Stavrakia, GR-711 10 Heraklion (Crete), Greece.Tel: 30 2810 392706; fax: 30 2810 542 055; e-mail: cardio@med.uoc.gr

The content of these European Society of Cardiology (ESC) Guidelines has been published for personal and educational use only. No commercial use is authorized.No part of the ESC Guidelines may be translated or reproduced in any form without written permission from the ESC. Permission can be obtained upon submissionof a written request to Oxford University Press, the publisher of the European Heart Journal and the party authorized to handle such permissions on behalfof the ESC.

Disclaimer. The ESC Guidelines represent the views of the ESC and were arrived at after careful consideration of the available evidence at the time they werewritten. Health professionals are encouraged to take them fully into account when exercising their clinical judgement. The guidelines do not, however, overridethe individual responsibility of health professionals to make appropriate decisions in the circumstances of the individual patients, in consultation with thatpatient, and where appropriate and necessary the patients guardian or carer. It is also the health professionals responsibility to verify the rules and regulationsapplicable to drugs and devices at the time of prescription.

European Heart Journal (2007) 28, 22562295doi:10.1093/eurheartj/ehm305

& The European Society of Cardiology 2007. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

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1.5.2. Congenital atrioventricular block . . . . . . 2270

1.5.3. Atrioventricular block and cardiac surgery . 22701.5.4. Long QT syndrome . . . . . . . . . . . . . . . 22701.5.5. Adults with congenital heart disease . . . . 2270

1.5.6. Device and mode selection . . . . . . . . . . 22711.6. Cardiac transplantation . . . . . . . . . . . . . 2271

2. Pacing for specific conditions . . . . . . . . . . . . 2272

2.1. Hypertrophic cardiomyopathy . . . . . . . . . . 2272

2.1.1. The rationale for short atrioventriculardelay DDD pacing in hypertrophicobstructive cardiomyopathy . . . . . . . . . 2272

2.1.2. Therapy delivery and programming . . . . . 2272

2.1.3. Indications for pacing in hypertrophicobstructive cardiomyopathy . . . . . . . . . 2273

2.2. Sleep apnoea . . . . . . . . . . . . . . . . . . . 2273

3. Cardiac resynchronization therapy in patients withheart failure . . . . . . . . . . . . . . . . . . . . . 2273

3.1. Introduction . . . . . . . . . . . . . . . . . . . . 2273

3.1.1. Rationale of cardiac resynchronization . . . 22733.1.2. Evidence-based clinical effects of cardiac

resynchronization therapy . . . . . . . . . . 2274

3.1.3. Cost-effectiveness issues . . . . . . . . . . . 22753.1.4. Unresolved issues . . . . . . . . . . . . . . . 22753.1.5. Programming recommendations . . . . . . . 2278

3.2. Recommendations . . . . . . . . . . . . . . . . 22783.2.1. Recommendations for the use of cardiac

resynchronization therapy by biventricular

pacemaker(CRT-P) or biventricular pacemakercombined with an implantable cardioverterdefibrillator (CRT-D) in heart failure patients . 2278

3.2.2. Recommendations for the use of biventricularpacing in heart failure patients with aconcomitant indication for permanent pacing 2278

3.2.3 Recommendations for the use of an

implantable cardioverter defibrillator

combined with biventricular pacemaker(CRT-D) in heart failure patients with an

indication for an implantable cardioverterdefibrillator . . . . . . . . . . . . . . . . . . 2278

3.2.4 Recommendations for the use of

biventricular pacing in heart failure patients

with permanent atrial fibrillation . . . . . . 2278Appendix A: pacemaker follow-up . . . . . . . . . 2278

The main objectives, structure, and functionof the pacemaker clinic . . . . . . . . . . . . . 2279

Pre-discharge assessment and long-termfollow-up methodology . . . . . . . . . . . . . . 2280Complications, failures, and side effects

of pacemaker treatment . . . . . . . . . . . . . 2280Special issues related to the pacedpatients life . . . . . . . . . . . . . . . . . . . 2280

Appendix B: technical considerations andrequirements for implanting cardiacresynchronization therapy devices . . . . . . . . . 2281

Technical and personnel requirements forcentres intending to implant cardiacresynchronization therapy devices . . . . . . . 2282

Scheduling patient for cardiacresynchronization therapy . . . . . . . . . . . . 2282

Characterization of coronary sinus anatomy . 2282

Requirements for the operating theatre . . . . 2282Personnel requirements during cardiac

resynchronization therapy implantation . . . . 2284

Clinical competence for implanting cardiacresynchronization therapy devices . . . . . . . 2284

Minimum training for competence . . . . . . 2284Maintenance of competence . . . . . . . . . 2285Further practical cardiac resynchronization

therapy implant recommendations . . . . . 2285Follow-up . . . . . . . . . . . . . . . . . . . . . 2285

Long-term follow-up . . . . . . . . . . . . . 2285

Abbreviations . . . . . . . . . . . . . . . . . . . . . 2286Clinical trial acronyms . . . . . . . . . . . . . . . . 2286References . . . . . . . . . . . . . . . . . . . . . . 2287

Preamble

Guidelines and Expert Consensus Documents summarize andevaluate all currently available evidence on a particularissue with the aim to assist physicians in selecting the bestmanagement strategies for a typical patient, sufferingfrom a given condition, taking into account the impact onoutcome, as well as the riskbenefit ratio of particular diag-nostic or therapeutic means. Guidelines are no substitutes

for textbooks. The legal implications of medical guidelineshave been discussed previously.A great number of Guidelines and Expert Consensus Docu-

ments have been issued in recent years by the EuropeanSociety of Cardiology (ESC) as well as by other societiesand organizations. Because of the impact on clinical prac-tice, quality criteria for development of guidelines havebeen established in order to make all decisions transparentto the user. The recommendations for formulating andissuing ESC Guidelines and Expert Consensus Documentscan be found on the ESC website (http://www.escardio.org/knowledge/guidelines/rules).

In brief, experts in the field are selected and undertake acomprehensive review of the published evidence for man-

agement and/or prevention of a given condition. A criticalevaluation of diagnostic and therapeutic procedures is per-formed including the assessment of the risk/benefit ratio.Estimates of expected health outcomes for larger societiesare included, where data exist. The level of evidence andthe strength of recommendation of particular treatmentoptions are weighed and graded according to pre-definedscales, as outlined in Tables 1and 2.

The experts of the writing panels have provided disclosurestatements of all relationships they may have which mightbe perceived as real or potential sources of conflictsof interest. These disclosure forms are kept on file at the

Table 1 Classes of recommendations

Class I Evidence and/or general agreement that a giventreatment or procedure is beneficial, useful, andeffective

Class II Conflicting evidence and/or a divergence of opinionabout the usefulness/efficacy of the giventreatment or procedure

Class IIa Weight of evidence/opinion is in favour ofusefulness/efficacy

Class IIb Usefulness/efficacy is less well established byevidence/opinion

Class III Evidence or general agreement that the giventreatment or procedure is not useful/effectiveand in some cases may be harmful

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European Heart House, headquarters of the ESC. Anychanges in conflict of interest that arise during the writingperiod must be notified to the ESC. The Task Force reportwas entirely supported financially by the ESC and was devel-oped without any involvement of the industry.

The ESC Committee for Practice Guidelines (CPG) super-vises and coordinates the preparation of new Guidelinesand Expert Consensus Documents produced by Task Forces,expert groups, or consensus panels. The Committee is alsoresponsible for the endorsement process of these Guidelines

and Expert Consensus Documents or statements. Once thedocument has been finalized and approved by all theexperts involved in the Task Force, it is submitted tooutside specialists for review. The document is revised,and finally approved by the CPG and subsequently published.

After publication, dissemination of the message is of para-mount importance. Pocket-sized versions and personaldigital assistant-downloadable versions are useful at thepoint of care. Some surveys have shown that the intendedend-users are sometimes not aware of the existence ofguidelines or simply do not translate them into practice sothis is why implementation programmes for new guidelinesform an important component of the dissemination ofknowledge. Meetings are organized by the ESC and directed

towards its member National Societies and key opinionleaders in Europe. Implementation meetings can also beundertaken at national levels, once the guidelines havebeen endorsed by the ESC member societies, and translatedinto the national language. Implementation programmes areneeded because it has been shown that the outcome ofdisease may be favourably influenced by the thorough appli-cation of clinical recommendations.

Thus, the task of writing Guidelines or Expert Consensusdocuments covers not only the integration of the mostrecent research, but also the creation of educational toolsand implementation programmes for the recommendations.The loop between clinical research, writing of guidelines,

and implementing them into clinical practice can thenonly be completed, if surveys and registries are performedto verify that real-life daily practice is in keeping withwhat is recommended in the guidelines. Such surveys andregistries also make it possible to evaluate the impact ofimplementation of the guidelines on patient outcomes.Guidelines and recommendations should help the physiciansto make decisions in their daily practice; however, the ulti-mate judgement regarding the care of an individual patientmust be made by the physician in charge of his/her care.

Introduction

Cardiac pacing has been used in the treatment of bradyar-

rhythmias for more than 50 years and during that time

both clinical practice and an impressive body of researchhave proved its effectiveness objectively, in terms of par-ameters that includes the patients quality of life, morbid-ity, and mortality. There can also be no doubt that therelated technology has made great strides over the sameperiod.14

Today, thanks to developments in microelectronics, thedevices are smaller, the programming options wider, and

the pacing leads thinner but longer lasting than before. Allthese developments, in both hardware and software, haveaimed at the primary goal of appropriate electrical correc-tion of pulse and conduction defects in such a way as tosimulate the natural, inherent electrical function of theheart as closely as possible and to satisfy the patientsneeds while minimizing side effects. In addition, increaseddevice longevity and the elimination of major and minorcomplications resulting from treatment have also been theconstant aims of both manufacturers and physicians.

During the last 12 years, electrical stimulation hasadvanced further, into the realm of ventricular resynchroni-zation as an adjunctive therapy for patients with

drug-refractory heart failure and ventricular conductiondelay. It must be remembered that cardiac pacing for bothbradyarrhythmia and cardiac resynchronization therapy(CRT) was first used clinically in Europe.4,5,264,265

The guidelines for the appropriate use of pacemakerdevices presented in this document, a joint EuropeanSociety of Cardiology (ESC) and EHRA initiative, aim toprovide for the first time in Europe an up-to-date specialistsview of the field. The guidelines cover two main areas: thefirst includes permanent pacing in bradyarrhythmias,syncope, and other specific conditions, whereas the secondrefers to ventricular resynchronization as an adjuncttherapy in patients with heart failure.

Pacing in bradyarrhythmia, syncope, and otherspecific conditions

The recommendations for pacing in bradyarrhythmias werebased on an extensive review of the literature, old andnew, with a view to reaching evidence-based conclusions.Where the literature is lacking, mainly with regard to con-ditions where no other therapy could replace pacing, therecommendations are based on expert consensus. Theguidelines that follow concern patients who have permanentand irreversible disturbances of the systems for generationand conduction of the cardiac stimulus. The text will oftenmake reference to the fact that the decision to implant a

device depends on the accurate judgement of the treatingphysician, who must determine whether the damage is ofa permanent and irreversible nature.

When the pathophysiology of the condition is judged to befully reversible, for example, in the case of drug effects(digitalis intoxication) or electrolyte disturbances, or mostlikely reversible, such as in inflammatory or ischaemic myo-cardial disease, the bradyarrhythmic condition should betreated initially without permanent implantable devicetherapy. Of course, in daily practice, the nature of the dis-turbances of stimulus production and conduction is oftenambiguous and the permanence of the condition is unclear.

As mentioned above, the focus of these guidelines is theappropriate use of pacemakers in patients with bradyar-

rhythmias. Obviously, the work of the committee would be

Table 2 Levels of evidence

Level ofevidence A

Data derived from multiple randomizedclinical trials or meta-analyses

Level ofevidence B

Data derived from a single randomized clinicaltrial or large non-randomized studies

Level ofevidence C

Consensus of opinion of the experts and/orsmall studies, retrospective studies, and

registries

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incomplete if it limited itself only to recommendations con-cerning indications for pacing and failed to include consider-ation of the proper pacing mode in each case. It wastherefore considered essential to cover in this report theproposed pacing modes for each condition.

On the other hand, the committee decided that the docu-ment should not include recommendations for the choice ofpacing leads or for their extraction or replacement. These

subjects will be covered by forthcoming EHRA documents.

Cardiac resynchronization therapy

Cardiac pacing as an adjunct therapy for heart failure beganto be the subject of scientific research at the start of the1990s. The first pacing modality to be examined was dual-chamber pacing with a short atrioventricular (AV) delay, inpatients with heart failure but without the classical bradyar-rhythmic indications for pacing. The first studies in this areagave promising results. Acute and short-term improvementsresulted from the optimization of left ventricular (LV) fillingand a reduction in pre-systolic mitral regurgitation. Unfortu-nately, the initial results were not confirmed by subsequent

studies and the early hopes raised by dual-chamber pacingwith a short AV delay for heart failure patients were notfulfilled.

In contrast, atrio-biventricular pacing for patients withsymptomatic heart failure and intra- or interventricular con-duction disturbances has proved beneficial. During the lastdecade, a number of studies have established a theoreticalbasis for this new therapy and have drawn related con-clusions regarding the importance of resynchronization interms of improving symptoms, morbidity, and mortality inthese patients.

This document presents the recommendations of the com-mittee concerning indications for CRT based on the most

recent studies.

1. Pacing in arrhythmias

1.1. Sinus node disease

Sinus node disease, also known as sick sinus syndrome, des-ignates a spectrum of sinoatrial dysfunction that rangesfrom the usually benign sinus bradycardia to sinus arrest orto the so-called bradycardiatachycardia syndrome.6 Thelatter is characterized by the development of paroxysmalatrial tachyarrhythmias in patients with sinus bradycardiaor sinoatrial block. Some patients with frequent, repetitive,long-lasting episodes, or atrial fibrillation (AF) may remodel

their atrial myocardium, including the sinoatrial region, andare prone to systemic embolism.7

In patients with sinus arrest, there may be an ectopicatrial or AV junctional escape rhythm. Some patients withsustained AF or flutter may have an underlying sinus nodedysfunction that becomes patent after cardioversion of theatrial tachyarrhythmia. An additional manifestation ofsinus node dysfunction is the lack of an adequate chronotro-pic response to exercise. Sinus node disease, as a clinicalentity, encompasses not only disorders of the sinus nodeimpulse formation or its conduction to the right atrium,but also a more widespread atrial abnormality that is thesubstrate for the development of atrial tachyarrhythmias.In addition, some patients with signs of sinus node dysfunc-

tion may also present AV conduction abnormalities.

We lack adequately controlled pathological studies todefine the structural basis of the sick sinus syndrome andits various clinical and electrocardiographic manifestations.Future studies must compare the structural changes in thesinoatrial region of patients with various forms of sinusnode disease, who otherwise have normal hearts, withappropriate controls matched for age and gender. To attri-bute specific pathological meaning to structural findings

observed in anecdotal necropsy reports on patients withsick sinus syndrome is openly speculative. To conduct patho-logical studies on the sinus node region is not a simple taskbecause of the complexity of this area.8 The sinus nodetissue is widely distributed at the junction between thesuperior vena cava and the right atrium, which probablyimplies that for the development of significant sinus nodedisease, an ample atrial architectural disorder is needed.

The most dramatic symptom of the disease is syncope ornear syncope, due to sinus arrest or sinoatrial block, whichmay often be reflex in nature.9

Sinus pauses may sometimes be followed by atrialtachyarrhythmias that are sufficiently rapid to prolong the

hypotension, causing syncope or dizziness. Apart fromthe above, it is not uncommon for the symptoms of thedisease to be limited to fatigue or dyspnoea, reduced exer-cise capacity, and cognitive impairment, as a consequenceof exaggerated bradycardia (,40 b.p.m.) and chronotropicincompetence.10,11 The latter is characterized by animpaired heart rate response to exercise and is generallydefined as failure to achieve 85% of the age-predictedmaximum heart rate.10,11

The diagnosis of sinus node disease is based on relating avariety of electrocardiographic findings with the symptoms.In some patients with syncope of undetermined origin, theunderlying mechanism is a symptomatic paroxysmal sinusnode dysfunction that cannot be easily demonstrated by

conventional 24 or 48 h Holter monitoring. In such patients,an implantable loop recorder may be the only way of estab-lishing the correct diagnosis. We should also take into con-sideration the interaction between sick sinus syndromeand neurally mediated syncope. Apart from syncopecaused by prolonged pause following the termination oftachycardia in the bradytachy syndrome, the vast majorityof the other syncopes are due to, or favoured by, an abnor-mal reflex. Moreover, if a persistent bradycardia clearlydefines sick sinus syndrome, the meaning of intermittentbradycardia and sinus arrest is less clear. Indeed, the sameevent (i.e. intermittent sinus arrest) may be diagnosed byone physician as intermittent sick sinus syndrome and by

another as cardioinhibitory neurally mediated syndrome. Ingeneral, the same syncope is diagnosed as neurally mediatedif not documented, whereas if there is the fortuitous docu-mentation of a pause, it is diagnosed as sick sinus syndrome.

Electrophysiological evaluation of sinus node functionincludes the measurement of the corrected sinus noderecovery time and the sinus node conduction time. It isbeyond the scope of these guidelines to review the sensi-tivity, specificity, and diagnostic accuracy of the variouscut-off points that have been advanced during the last25 years for these two sets of parameters.

1.1.1. Indications for pacing in sinus node diseaseOncesinusnodedisease,mildorsevere,isdiagnosed,theques-

tion arises whether to implement permanent pacing or not.

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Long experience, together with a number of studies, hasshown that pacing in sinus node disease contributes moreto relieving symptoms and reducing the episodes of AF1216

than to reducing mortality in these patients.1719

The indications for pacing in sinus node disease, on thestrength of evidence in the available older and modern lit-erature, are given in Table 1.1.1. It is important to notehere that when sinus node disease is diagnosed, atrial

tachyarrhythmias are likely, even if not recorded, so thatapart from pacing serious consideration should be given tooral anticoagulation therapy if not contraindicated.20

1.1.2. Choice of the pacing mode for patientswith sinus node diseaseDuringthe last twodecades,severalclinical endpoint trials, aswell as developments in pacing devices, have increased ourknowledge and expanded the possibilities for optimal pacingtherapy in patients with symptomatic sinus node disease.The principal endpoints of those trials, comparing atrial withventricular based pacing, were mortality, AF, frequency of

thrombo-embolic episodes and stroke, heart failure, pace-maker syndrome, and the patients quality of life.

The first randomized trial to address these matters was byAndersenet al.21 They studied 225 patients with sinus nodedisease and intact AV conduction, who were assigned ran-domly to either atrial or ventricular pacing. At the end ofa 5.5-year period, the patients who were paced in AAImode had significantly lower incidences of AF,thrombo-embolic events, heart failure, cardiovascular mor-tality, and total mortality, compared with those paced in VVImode. Two things were unique about that study: it was theonly randomized study to date that compared pure AAI andVVI modes over a long follow-up period and it was also the

only one to show a clear benefit in terms of all the clinicalparameters examined, and primarily in mortality, forpatients who had atrial pacing.

The following studies examined the role of VVI comparedwith DDD mode in this patient population. Lamas et al.,22 inthe PAcemaker Selection in the Elderly (PASE) trial, studied407 patients who were paced for a variety of indications,including 175 who suffered from sinus node dysfunction.All patients received a dual chamber, rate adaptivesystem, which was randomly programmed to either VVIR orDDDR mode, and were studied prospectively for 2.5 years.The results showed no statistically significant differencebetween the two modes of pacing as regards the incidenceof thrombo-embolic episodes, stroke, AF, or the patients

quality of life, for the patient population as a whole.There was a non-significant trend favouring atrial-basedpacing in the subgroup with sinus node disease. However,the short follow-up of the study, the very large crossoverfrom VVIR to DDDR and the problem of intention to treatanalysis must be taken into consideration.

The Canadian Trial of Physiological Pacing (CTOPP),23 aprospective, randomized study, compared the clinical out-comes in 2568 patients who were randomized to atrialbased or ventricular pacing for a mean follow-up period of3.5 years. The study found no significant differencebetween the two treatment groups in the combined inci-dence of stroke or death or in the likelihood of hospitaliz-

ation for heart failure. However, after 2 years offollow-up, physiological pacing was associated with an 18%relative reduction in the development of chronic AF. A sub-group of patients who were paced for sinus node dysfunctionshowed no trend towards a benefit from atrial-based pacingin terms of mortality or stroke.

Finally, the Mode Selection Trial (MOST)24 in sinus nodedysfunction studied prospectively 2010 patients who wererandomized to either DDDR or VVIR mode and were followedfor a mean period of 2.7 years. There were no statisticallysignificant differences between the groups in the incidenceof death or stroke, but there was a 21% lower risk of AF, a27% lower risk of hospitalization for heart failure and abetter quality of life in the DDDR group, compared with

those paced in VVIR mode. Importantly, the study also

Table 1.1.1 Recommendations for cardiac pacing in sinus nodedisease

Clinical indication Class Level of evidence

1. Sinus node disease manifests assymptomatic bradycardia with orwithout bradycardia-dependanttachycardia. Symptomrhythmcorrelation must have been:

Class I C

spontaneously occurringdrug induced where alternative drugtherapy is lacking

2. Syncope with sinus node disease,either spontaneously occurring orinduced at electrophysiological study

3. Sinus node disease manifests assymptomatic chronotropicincompetence:

spontaneously occurringdrug induced where alternative drug

therapy is lacking1. Symptomatic sinus node disease,which is either spontaneous or inducedby a drug for which there is noalternative, but no symptom rhythmcorrelation has been documented.Heart rate at rest should be,40 b.p.m.

Class IIa C

2. Syncope for which no otherexplanation can be made but there areabnormal electrophysiological findings(CSNRT . 800 ms)

1. Minimally symptomatic patients withsinus node disease, resting heart rate,40 b.p.m. while awake, and no

evidence of chronotropicincompetence

Class IIb C

1. Sinus node disease without symptomsincluding use of bradycardia-provokingdrugs

Class III C

2. ECG findings of sinus node dysfunctionwith symptoms not due directly orindirectly to bradycardia

3. Symptomatic sinus node dysfunctionwhere symptoms can reliably beattributed to non-essentialmedication

When sinus node disease is diagnosed, atrial tachyarrhythmias are likelyeven if not yet recorded, implying that serious consideration should begiven to anticoagulant therapy.

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which is drug induced, and palpitations. Selection of pacingmode and device is more complex, but the trend is towardsdual-chamber pacing with minimization of right ventricularstimulation (in order to avoid changes leading to desynchroni-zation of the ventricles as a result of their being depolarizedfrom the right ventricular apex), rate modulation (RR), and apanoply of antitachycardia algorithms possibly combined withstimulation of the atria from the septum rather than the

appendage (Figure 1). However, no consistent data fromlarge randomized trials support the use of alternative single-site atrial pacing, multisite right atrial pacing, or biatrialpacing in sinus node disease patients. Ventricular pacingalone can no longer be recommended, and furthermore, dual-chamber pacing increases quality-adjusted life expectancy ata cost that is generally considered acceptable.34 Regardingthe choice of AAI or DDD pacemaker implantation, weshould take into consideration that although DDD is moreexpensive, there is a possibility, albeit small (1% of annualincidence), of the future development of AV block.35,36

1.2. Atrioventricular and intraventricular

conduction disturbances

In AV block, atrial activation is conducted to the ventricleswith a delay, or is not conducted at all, during a periodwhen the AV conduction pathway (AV node or His-Purkinjesystem) is not expected to be refractory. Traditionally, onthe basis of the electrocardiographic criteria, AV block isclassified as first, second, or third degree, and dependingon the anatomical point at which the conduction of the acti-vation wavefront is impaired, it is described as supra-Hisian,intra-Hisian, or infra-Hisian.

In the first-degree AV block, every atrial stimulus is con-ducted to the ventricles, but the PR interval is prolongedto .200 ms. The conduction delay may occur at the level

of the AV node or at the His-Purkinje system. If the QRScomplex is narrow, the conduction delay is usually in theAV node and rarely within the His bundle. If the QRS iswide, the conduction delay may be either in the AV nodeor in the His-Purkinje system and only a His bundle electro-gram can locate it precisely.

A second-degree AV block is characterized by the fact thatone or more atrial stimuli are not conducted to the ventri-cles. It is divided into type I, or Wenckebach, or Mobitz I,and type II, or Mobitz II AV block. In type I, the electrocar-diogram (ECG) shows a progressively increasing PR intervaluntil an atrial stimulus fails to be conducted to the ventri-cles. Often, the increase in the PR interval is subtle in the

last cardiac cycles before the blocked P wave and can onlybe recognized in comparison with the shortest PR interval,which usually follows the blocked P wave. The delay isusually in the AV node and deterioration to a higherdegree of AV block is uncommon. However, in cases with awide QRS complex, an electrophysiological study is requiredto determine the level of the block. In type II AV block, pro-vided there is normal sinus rhythm, the PR interval is con-stant before and after the blocked P wave. In this type,the conduction block is usually in the His-Purkinje system,especially in the case of a wide QRS.

In complete (third-degree) AV block, no atrial stimulus isconducted to the ventricles and the ventricles are depolar-ized by an escape rhythm. Although the escape rate may

have significance for the development of symptoms, the

site of escape rate origin is of major importance forpatients safety (i.e. in the AV node, intra- or infra-Hisian).

AV block was the first indication for pacing, and today, itremains one of the most common reasons for pacemakerimplantation. Nevertheless, because of the lack of large,comparative, randomized studies, there are still open ques-tions about the indications for pacing, others that concernthe pacing mode, and numerous issues regarding the lead

implantation site. The decision to implant a pacemaker isbased, to a large extent, on the presence of symptomsthat are directly related to the bradycardia caused by theAV block. The situation may become even more complexwhen the conduction disturbance is intermittent. In such acase, the information provided by the surface ECG islimited and a 24 h Holter ECG recording, or even longerrhythm recordings using an external or implantable looprecorder, may be required.

1.2.1. Indications for pacingIn the case of complete AV block, there are a number of non-randomized studies showing that permanent cardiac pacing

improves survival, especially in patients who experienceepisodes of syncope.3742 In type I second-degree AV block,the indications for permanent pacing are controversial,unless the conduction delay occurs below the AV node orthere are symptoms.43,44 However, some authors suggestthat pacemaker implantation should be considered even inthe absence of symptomatic bradycardia or organic heartdisease, because survival is significantly better for pacedthan for unpaced asymptomatic elderly patients, especiallywhen type I second-degree AV block occurs during diurnalhours.45

In type II second-degree block, especially when there isalso a wide QRS, progression to complete heart block andthe appearance of symptoms are common;43,46,47 thus

pacing is recommended. In patients with first-degree AVblock, cardiac pacing is not recommended unless the PRinterval fails to adapt to heart rate during exercise and islong enough (usually .300 ms) to cause symptoms becauseof inadequate LV filling, or an increase in wedge pressure,as the left atrial systole occurs close to or simultaneouswith the previous LV systole. In such cases small, uncon-trolled studies have shown an improvement in patientssymptoms.48,49

It should be noted that before the decision for permanentpacing is made, it should be checked whether the AV block isdue to a reversible cause, such as acute myocardial infarc-tion, electrolytic disturbances, drugs that can be discontin-

ued (digoxin, non-dihydropyridine calcium channel blockers,beta-blockers, and so on), sleep apnoea, peri-operativehypothermia, or inflammation or vagotonia arising fromfactors that can be avoided.

1.2.2. Acquired atrioventricular block

in special casesDistal AV block may be observed during effort and, if not dueto ischaemia, it is probably caused by damage to the His-Purkinje system and has a poor prognosis.50,51 In this case,permanent pacing is recommended, as it is also in patientswho suffer from a progressively deteriorating conditionsuch as amyloidosis, sarcoidosis, or neuromuscular dis-eases.5258 Pacing is also recommended in patients develop-

ing permanent AV block as a complication of a catheter

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1.3. Recent myocardial infarction

1.3.1. Pacing in conduction disturbances relatedto acute myocardial infarctionThe major conduction abnormalities associated with acutemyocardial infarction include AV block and intraventricular

conduction disturbances.

115118

They are the result of bothautonomic imbalance and ischaemia or necrosis of the con-duction structure.

Despite the development of new methods for the manage-ment of acute myocardial infarction (including thrombolysisand percutaneous coronary intervention), the incidence ofintraventricular conduction disturbances has not changedsignificantly, whereas the incidence of AV block hasdecreased but remains still high.115,116,119122

Data from 75 993 patients enrolled in four large, random-ized, clinical trials (GUSTO-I, GUSTO-IIb, GUSTO-III, andASSENT-II) suggest that AV block occurs in almost 7% ofcases of acute myocardial infarction.119 Patients with peri-infarction AV block have higher in-hospital and late mor-

tality than do those with preserved AV conduction.119

Similarly, data regarding the incidence of intraventricularconduction abnormalities in patients with an acute myocar-dial infarction treated with thrombolytic agents suggest thatthe incidence of bundle branch block has not been alteredsignificantly by thrombolytic therapy, occurring in a transi-ent form in up to 18.4% of patients and in a persistent

form in up to 5.3%.

122

Conduction disturbances carry a poor prognosis, with asignificant increase in the mortality rate even in the throm-bolytic era.115122 The increase in mortality risk is largelyseen within the first 30 days in the setting of both an inferiorand an anterior myocardial infarction. However, when AV orintraventricular conduction block complicates acute myo-cardial infarction, the long-term prognosis for survivors isrelated primarily to the extent of myocardial injury, thedegree of heart failure, and the higher incidence of haemo-dynamic complications.115123

The location of the infarct influences the type of conduc-tion disturbances in the setting of an acute myocardialinfarction. AV block associated with inferior wall infarction

is located above the His bundle in the vast majority of

Figure 2 Pacemaker mode selection in acquired atrioventricular, chronic bifascicular, and trifascicular block. When atrioventricular block is not permanent,pacemakers with algorithms for the preservation of native atrioventricular conduction should be selected. *VVIR could be an alternative, especially in patientswho have a low level of physical activity and in those with a short expected lifespan.

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patients, whereas AV block associated with anterior wallmyocardial infarction is more often located below the AVnode.124 Thus, the former is usually associated with transi-ent bradycardia, with a narrow QRS escape rhythm above40 b.p.m. and low mortality, whereas the latter is associ-ated with an unstable, wide QRS escape rhythm and extre-mely high mortality (up to 80%) due to the extensivemyocardial necrosis. Intraventricular conduction disturb-

ances are more commonly developed in the setting of ananterior-anteroseptal infarction as a result of specificblood supply conditions.118,124 Their presence during anacute myocardial infarction is associated with an unfavour-able short- and long-term prognosis and an increased riskof sudden cardiac death (SCD).

The nature and prognosis of conduction disturbances fol-lowing an acute myocardial infarction are somewhat distinctfrom other forms of conduction abnormalities. Moreover,indications for permanent pacing after acute myocardialinfarction are related to the coexistence of AV block andintraventricular conduction defects.40,125,126 We must keepin mind that in patients with an inferior wall infarction con-

duction abnormalities may be transient (resolution within7 days) and are often well tolerated.127,128 Therefore, insuch circumstances, there is generally no need for pacemakerimplantation. Recommendations for cardiac pacing in per-sistent conduction disturbances (more than 14 days)related to acute myocardial infarction are summarized inTable 1.3.1.

In the context of thrombolysis and revascularization, dataon persistence of conduction abnormalities and prognosisare lacking. Arbitrary definitions of transience and persist-ence have been proposed. Mobitz II with bundle branchblock and third-degree AV block with wide QRS in post-myocardial infarction patients are considered to have a simi-larly poor prognosis.

1.4. Reflex syncope

Reflex syncope includes a wide spectrum of different enti-ties that share common mechanisms (vasodilation and/orbradycardia). It is considered to be the consequence of areflex that, when triggered, induces an acute, inappropriateresponse mediated by the autonomic nervous system. Themain causes of reflex syncope are shown in Table 1.4.1. In

this pathology syncope is the only symptom that mayjustify pacemaker implantation. This excludes dizziness,light-headedness and vertigo, which are beyond the scopeof pacing therapy even in patients with an abnormalresponse to tests considered to be diagnostic of reflexsyncope. Syncope should be diagnosed according to the defi-nition in the syncope guidelines published by the ESC,129 asfollows: Syncope is a symptom, defined as a transient, self-limited loss of consciousness, usually leading to falling. Theonset is relatively rapid, and the subsequent recovery isspontaneous, complete, and usually prompt. The underlyingmechanism is transient global cerebral hypoperfusion.

Although some patients with orthostatic hypotension orsituational syncope have been treated by implantation of a

permanent pacemaker, the series is too limited and theresults too contradictory130133 to warrant separate con-sideration in the present guidelines. These autonomic dis-eases, which cause syncope mainly via major hypotensionand/or bradycardia, are not presently a recognized indi-cation for pacing, even though some individuals mightbenefit.130,134 This discussion will be restricted to the roleof pacing in patients with carotid and vasovagal syndromes,with a mention of adenosine sensitive syncope.

1.4.1. Carotid sinus syndromeIt has long been observed that pressure at the site where thecommon carotid artery bifurcates produces a reflex that

leads to a slowing of heart rate and a fall in blood pressure(BP). Some patients with syncope exhibit an abnormalresponse to carotid massage.135,136 A ventricular pauselasting 3 s or more and a fall in systolic BP of 50 mmHg ormore is considered abnormal and define carotid sinus hyper-sensitivity.137139 Carotid sinus massage is a tool used todemonstrate carotid sinus syndrome in patients withsyncope; its precise methodology and results are reportedin the guidelines for syncope.129 It should be emphasizedthat the reproduction of symptoms during the massage isnecessary to diagnose carotid sinus syndrome, whereas

Table 1.3.1 Recommendations for permanent cardiac pacing inconduction disturbances related to acute myocardial infarction

Clinical indication Class Level of evidence

1. Persistent third-degree heart blockpreceded or not by intraventricularconduction disturbances115,125,126,128

Class I B

2. Persistent Mobitz type IIsecond-degree heart blockassociated with bundle branch

block, with or without PRprolongation125128

3. Transient Mobitz type II second- orthird-degree heart block associatedwith new onset bundle branchblock127,128

None Class IIaNone Class IIb1. Transient second- or third-degree

heart block without bundle branchblock125,128

Class III B

2. Left anterior hemiblock newlydeveloped or present on admission128

3. Persistent first-degreeatrioventricular block128

Table 1.4.1 Main causes of reflex syncope (adapted fromBrignoleet al.129)

Vasovagal syncope (common faint)Carotid sinus syncopeSituational syncope

Acute haemorrhage (or acute fluid depletion)Cough and sneezeGastrointestinal stimulation (swallowing, defecation, andvisceral pain)Micturition (post-micturition)Post-exercisePost-prandialOthers (e.g. brass instrument playing and weightlifting)

Glossopharyngeal neuralgia

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without this the diagnosis is carotid hypersensitivity.140

Although carotid sinus syndrome is recognized as a potentialcause of spontaneous syncope, it is still under investigationin the current clinical practice and is therefore probablyunderestimated.

1.4.1.1. Indications for pacing in carotid sinus syndrome

The first reports of the abolition of syncope in carotid sinus

syndrome by permanent pacing appeared in the 1970s.141,142

Subsequent investigations,143,144 including non-randomizedcomparative studies,145 showed that pacing in such patientscould significantly reduce the number of syncopal episodes,and in the mid-1980s, pacing became the approved treat-ment. The first randomized trial comparing pacing and nopacing was reported in the 1990s.146 This study included60 patients: 32 were included in the pacemaker arm(18 patients with VVI and 14 patients with DDD pacemaker)and 28 in the no treatment group. After a mean follow-upof 36+10 months, syncope recurred in 9% of the pace-maker group, compared with 57% in the untreated patients(P, 0.0002). In another study, patients with a cardioinhibi-tory response to carotid sinus massage received a pace-

maker that was designed to record asystolic episodes. Longpauses (.6 s) were detected in 53% of the patients during2 years follow-up, suggesting that a positive response tocarotid massage predicts the occurrence of spontaneouslong ventricular pauses147 and that pacing therapy is ableto prevent the symptoms of these long pauses. Since drugtherapy for cardioinhibitory carotid sinus syndrome hasbeen abandoned,148 cardiac pacing appears to be the solebeneficial treatment for these patients,143146 in spite ofthere being only one positive randomized trial with a rela-tively small number of patients.147 Recommendations forcardiac pacing in carotid sinus syndrome are summarizedin Table 1.4.2.

1.4.1.2. Choice of the pacing mode in carotidsinus syndrome

Although it has been argued that single-chamber ventricularpacing may be sufficient in those relatively infrequent caseswhere there is neither a marked vasodepressor componentto the reflex nor a so-called ventricular pacing effect,149

when pacing is prescribed dual-chamber cardiac pacingis preferred.144,150 Some dual-chamber pacemakers withsophisticated algorithms were specially designed to limitthe effects of hypotension consequent to vasodilation.The algorithms were based on acceleration of the pacingrate when intrinsic heart rate suddenly decreases. Althoughacute results were in favour of these algorithms,151 there is

no well-designed trial demonstrating that they are superiorto simple rate hysteresis during long-term pacing.

1.4.2. Vasovagal syncopeVasovagal syncope accounts for 50% of all the cases ofpatients admitted for this symptom.152154 In the vastmajority, the clinical history is sufficiently typical towarrant the diagnosis without additional investigations.However, in some cases, tilt testing remains the key investi-gation used to diagnose the vasovagal origin of syncope. Themethodology, complications and criteria for a positiveresponse to tilt testing have already been reported indetail.129 Many studies have assessed the role of tilttesting in treatment selection, including pacing for vasova-

gal syncope. Data from controlled trials showed that 50%

of patients with a baseline positive tilt test became negativewhen the test was repeated, whether the patient wasreceiving treatment or placebo.155157 Moreover, acutestudies were not predictive of the long-term outcome ofpacing therapy.156 Finally, the mechanism of tilt-inducedsyncope was frequently different from that of spontaneoussyncope recorded by an implantable loop recorder.158

These data show that tilt testing is of little or no value forassessing the effectiveness of treatments, particularlypacing.

1.4.2.1. Non-pacing therapy in vasovagal syncope

Despite vasovagal syncope being the most frequent of allcauses of fainting, present treatment strategies are basedon an incomplete understanding of the pathophysiology ofthe faint. In the majority of cases, patients who seekmedical advice after having experienced vasovagalsyncope mainly require reassurance and education regardingthe benign nature of the condition. In particular, based on areview of their medical history, patients should be informedof the likelihood of syncope recurrence. Initial counsellingshould also include advice about adequate hydration andpre-monitory symptoms that may allow individuals to recog-nize an impending episode, so that they may take measures,such as lying down or using isometric manoeuvres, to avertor limit the consequence of a loss of consciousness. Pharma-

cological treatments in patients with vasovagal syncope,

Table 1.4.2 Recommendations for cardiac pacing in carotidsinus syndrome

Clinical indication Class Level of evidence

Recurrent syncope caused byinadvertent carotid sinus pressure

and reproduced by carotid sinusmassage, associated withventricular asystole of more than 3 sduration (patient may be syncopalor pre-syncopal), in the absence ofmedication known to depress sinusnode activity

Class I C

Recurrent unexplained syncope,without clear inadvertent carotidsinus pressure, but syncope isreproduced by carotid sinusmassage, associated with aventricular asystole of more than 3 sduration (patient may be syncopalor pre-syncopal), in the absence of

medication known to depress sinusnode activity145149

Class IIa B

First syncope, with or without clearinadvertent carotid sinus pressure,but syncope (or pre-syncope) isreproduced by carotid sinusmassage, associated with aventricular asystole of more than 3 sduration, in the absence ofmedication known to depress sinusnode activity

Class IIb C

Hypersensitive carotid sinus reflexwithout symptoms

Class III C

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generally effective in non-randomized trials, have been con-sistently disappointing in randomized series.159,160

1.4.2.2. Indications for pacing in vasovagal syncope

Non-randomized trials. The rationale behind pacing forpatients with vasovagal syncope is based upon the frequentobservation of spontaneous, or tilt-induced, long ventricularpauses in those patients. However, head-up tilt findings have

generally shown that pacing fails to prevent syncope,although it may prolong the prodrome.161,162 Nevertheless,pacing has been the object of a number of both small andlarge observational studies, either in single or multiplecentres,161164 demonstrating effectiveness in highlyselected patient populations.

Randomized trials. The effectiveness of pacing has beenstudied in five multi-centre, randomized, controlledtrials:165169 the three non-blinded trials165167 produced posi-tive findings, whereas the two blinded studies168,169 had nega-tive results. The strongest supportive evidence was providedby the North American Vasovagal Pacemaker Study (VPS)166

and the European VASIS trial.165 In the randomized, controlled

Syncope Diagnosis and Treatment Study (SYDIT),167

the controlarm patients were treated with atenolol and the pacemakerwas superior to the beta-blocker in preventing recurrencesof syncope. After the publication of these three trials,pacing was considered to be a tenable treatment for patientswith frequent vasovagal syncope. However, both the VPS II168

and the Vasovagal Syncope and Pacing Trial (Synpace)169 pro-duced contradictory findings. They differed from the previoustrials because patients in the control arm received a perma-nent pacemaker that was switched off. Although there was a30% reduction in syncope recurrence rate (95% CI 233 to63%),the VPS II study failed to demonstrate a significant super-iority for pacemaker therapy. In the Synpace study, syncoperecurred in 50% of patients assigned to an active pacemaker

and in 38% of patients assigned to an inactive pacemaker. Asreported in the European guidelines for syncope,129 if theresults of the five trials are put together, 318 patients wereevaluated and syncope recurred in 21% (33/156) of thepaced patients and in 44% (72/162) of the unpaced patients(P, 0.001). However, all the studies had weaknesses andfurther follow-up studies addressing manyof these limitations,in particular the pre-implant selection criteria of patients whomight benefit from pacemaker therapy, need to be completedbefore pacing can be considered an effective therapy inselected groups of patients with recurrent vasovagal syncope.

The inadequate effectiveness of pacing should not be sur-prising, since pacing can be expected to correct ventricular

pauses but it cannot prevent hypotension due to vasodila-tion, which is frequently the dominant mechanism leadingto loss of consciousness in vasovagal syncope. A recentstudy using the implantable loop recorder158 concludedthat only about half of the patients had an asystolic pauserecorded at the time of spontaneous syncope. The role ofthe implantable loop recorder in the selection of patientswho may possibly benefit from cardiac pacing was evaluatedin the ISSUE 2 study,170 which confirmed earlier data158 indi-cating that patients selected on the basis of asystolic spon-taneous syncope on implantable loop recorder can benefitfrom pacing. In any case, it must be underlined that thedecision to implant a pacemaker needs to be kept in theclinical context of a benign condition, which frequently

affects young patients in whom pacemakers and leads for

several decades may be associated with complications.Thus, cardiac pacing should be confined to an extremelyselect small group of patients affected by severe recurrentvasovagal syncope and prolonged asystole during Holterrecording and/or tilt testing. Recommendations for cardiacpacing in vasovagal syncope are summarized inTable 1.4.3.If pacing is judged desirable for the treatmentof vasovagal syncope, the device used should be one thathas the capacity for programming modes that pace the ven-tricle whenever mandatory, from one cycle to the next(DDIRhysteresis, DDD/AMC, DDDAVD hysteresis),165 and

control abrupt rate drops (rate drop response, rate smooth-ing, flywheel, etc.).166,167 It has been shown in small seriesthat pacemakers with haemodynamic sensors (intracardiacimpedance and peak endocardial acceleration) have thecapability to diagnose the vasovagal episode earlier thanat the moment of rate drop. AAI-like algorithms arecontraindicated.

1.4.3. Adenosine-sensitive syncopeMany series that included extensive evaluation have shownthat 2030% of patients with syncopal episodes have noprecise diagnosis.153,171 This observation has led to newtests for the investigation of patients with syncope of

unknown origin. Among these, injection of an intravenousbolus of 20 mg adenosine was considered useful and hasgained some acceptance.172,173 The methodology and posi-tive criteria of the test have been reported.129,172,173

Although there was no agreement as to the positive criteria,there was a decrease in the number of patients without adiagnosis at the end of an extensive workup (probablybetween 5 and 10%). The only abnormal finding was anabnormally long ventricular pause during the adenosineinjection. This long pause, lasting more than 6173 or.10 s172 was due to the sudden onset of AV block. Patientsselected on the grounds of that finding underwent implan-tation of a permanent pacemaker. The therapy was testedin one randomized series of 20 patients.175 The results

were in favour of pacing: after a mean follow-up of 52

Table 1.4.3 Recommendations for cardiac pacing in vasovagalsyncope

Clinical indication Class Level of evidence

None Class I1. Patients over 40 years of age with

recurrent severe vasovagal syncopewho show prolonged asystole duringECG recording and/or tilt testing,after failure of other therapeuticoptions and being informed of theconflicting results of trials

Class IIa C

2. Patients under 40 years of age withrecurrent severe vasovagal syncopewho show prolonged asystole duringECG recording and/or tilt testing,after failure of other therapeuticoptions and being informed of theconflicting results of trials

Class IIb C

1. Patients without demonstrablebradycardia during reflex syncope

Class III C

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months, no patient had recurrences in the paced group,whereas syncope was reported by six patients in the nopacing group (P, 0.02). Assessment of these favourableresults was complicated by the observation of cardiacrhythm during a syncopal recurrence registered by animplantable loop recorder: only 50% of the patients had bra-dycardia.174,176,177 Finally, so far, there has been no well-designed randomized study able to determine the utility of

pacing in patients with a positive ATP test,129 thus no defini-tive recommendations can be made.

1.5. Paediatrics and congenital heart diseases

The indications for permanent cardiac pacing in childrenand adolescents, despite their similarities with those foradults, comprise a separate heading, under which a numberof determining factors must be taken into account beforethe decision is made to implant a permanent pacingdevice178180 (Table 1.5.1).

The logic behind the decision to pace will be based on thepatients age and symptoms, the kind of disease and its

natural history, and the possible coexistence of structural,congenital heart disease. The main indications for pacingin patients of this age are symptomatic bradycardia, brady-cardiatachycardia syndrome, congenital third-degree AVblock, surgical or acquired, advanced second- or third-degree AV block, and long QT syndrome.

In any case, the decision to pace an infant, child, or ado-lescent is not an easy one, since apart from the technicalpeculiarities that are often associated with the procedure,concerns may often arise regarding the inadequacy of thepacing system with the growth of the child and the psycho-logical issues raised by the patient or family. Nevertheless,at the same time, it is clear nowadays that any unreasonable

postponement of the decision to pace, which leaves thepatient with slow nodal or ventricular escape rhythms,often leads to further structural and functional heart prob-lems and may expose the patient to the risk of suddendeath.

Table 1.5.1 Recommendations for cardiac pacing in paediatricsand congenital heart disease

Clinical indication Class Level of evidence

1.Congenital third-degreeatrioventricular block with any of the

following conditions:

Class I B

SymptomsVentricular rate ,5055/min ininfantsVentricular rate ,70/min incongenital heart diseaseVentricular dysfunctionWide QRS escape rhythmComplex ventricular ectopyAbrupt ventricular pauses .23basic cycle lengthProlonged QTcPresence of maternalantibodies-mediated block188198

Continued

Table 1.5.1. Continued

Clinical indication Class Level of evidence

2. Second- or third-degreeatrioventricular block with

Class I C

Symptomatic bradycardiaa

Ventricular dysfunction3. Post-operative Mobitz type II second- or

third-degree block which persistsat least 7 days after cardiacsurgery199,200

Class I C

4. Sinus node dysfunction with correlationof symptoms184186

Class I C

1. Asymptomatic sinus bradycardia in thechild with complex congenital heartdisease and

Class IIa C

Resting heart rate ,40/min orPauses in ventricular rate .3 s184186

2. Bradycardiatachycardia syndromewith the need of antiarrhythmics whenother therapeutical options, such as

catheter ablation, are not possible187

Class IIa C

3. Long QT syndrome with Class IIa B2:1 or third-degree atrioventricularblockSymptomatic bradycardiaa

(spontaneous or due to beta-blocker)Pause-dependent ventriculartachycardia201203

4. Congenital heart disease and impairedhaemodynamics due to sinusbradycardiaa or loss of atrioventricularsynchrony

Class IIa C

1. Congenital third-degreeatrioventricular block without a Class Iindication for pacing188198

Class IIb B

2. Transient post-operative third-degreeatrioventricular block with residualbifascicular block

Class IIb C

3. Asymptomatic sinus bradycardia in theadolescent with congenital heartdisease and

Class IIb C

Resting heart rate ,40/min orPauses in ventricular rate .3 s184186

4. Neuromuscular diseases with anydegree of atrioventricular blockwithout symptoms

Class IIb C

1. Transient post-operativeatrioventricular block with return ofatrioventricular conduction within7 days199,200

Class III B

2. Asymptomatic post-operativebifascicular block with and withoutfirst-degree atrioventricular block

Class III C

3. Asymptomatic type I second-degreeatrioventricular block

Class III C

4. Asymptomatic sinus bradycardia in theadolescent with minimum heart rate.40/min and maximum pause inventricular rhythm ,3 s184186

Class III C

aClinical significance of bradycardia is age-dependent.

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in 168 adults with congenital heart disease. Forty-five percent of patients required pacing peri-operatively. The indi-cation for pacemaker implantation was AV block in 65%,sinus node dysfunction in 29%, and long QT or tachycardiain the remainder. At first implant, 63% of patients werepaced endocardially. Difficulty with vascular access wasfound in 15% of patients as a consequence of anomalousveins, previous surgery, or venous obstruction. A dual-

chamber pacemaker was used for the initial implant in 42%of patients, whereas 14% were upgraded in the follow-up.In this cohort of patients, 45% of them remained at risk foratrial arrhythmias regardless of pacing mode.

1.5.6. Device and mode selectionIn patients with AV block and normal ventricular function orin small children, ventricular rate-responsive demand pacing(VVIR) is sufficient for maintaining good cardiac function inmost patients. In small children, the presence of two leadsin the subclavian vein or superior vena cava might cause ahigh risk for thrombosis and venous occlusion. In adoles-cence and young adulthood, the system may be upgraded

to a dual-chamber one. Ventricular dysfunction or overtheart failure, pacemaker syndrome, and other symptomsrelated to chronic asynchrony between atrial and ventricu-lar contraction are common indications for conversion to adual-lead pacing system.178180,204208 Single-lead VDDpacing is possible in growing children with third-degree AVblock. It provides atrial synchronous endocardial pacingwithout the need for a two-lead system and is recommendedfor young patients with impaired AV conduction as a viablealternative to a dual-lead pacing system.

New data show that DDD and VDD pacing may have thelong-term detrimental effect of asynchronous electrome-chanical activation induced by apical right ventricularpacing, resulting in deleterious LV remodelling. Alternativesites of pacing should be considered.209

The higher heart rate level in infants and children com-pared with adults results in an increase in current drain,especially in the presence of high pacing thresholds. Inthese patients, especially automatic pacing threshold deter-mination and subsequent output regulation increases pacingsafety, decreases current drain, and prolongs battery life.210

In children and adolescents, AV and intraventricular con-duction delay is frequently observed after complex congeni-tal heart surgery; in some of them, CHF is present. In suchselected cases and also in patients with dilated cardiomyo-pathy when substantial LV dyssynchrony is present, CRTseems to be feasible and effective.211213 Clinical experi-

ence with CRT in young patients remains very limited todate. Recently, Dubin et al.212 presented a review of retro-spective multi-centre experience in 52 patients from 13institutions. They found that CRT appears to offer benefitin a paediatric and congenital heart disease population.

1.6. Cardiac transplantation

The aims of permanent pacing in cardiac transplant patientsare three-fold:

chronotropic support; coordination of cardiac chambers to improve mechanical

performance; rejection monitoring.

Bradyarrhythmias are common in the early post-transplant period and are encountered in up to 64% of reci-pients.214216 Permanent pacemaker implantation rates varyfrom 2.8 to 29% based on the criteria used.215,217 However,the surgical technique has been shown to have an importantimpact on the occurrence of sinus node dysfunction.218,219

For example, a shift from standard atrial anastomosis tobicaval anastomosis has significantly reduced the need for

pacemaker implantation.218,219

Sinus node dysfunction is the most frequent indication forpermanent pacing in cardiac transplant patients.216,219 Poss-ible causes of sinus node dysfunction include surgicaltrauma, sinus node artery damage, or ischaemia and pro-longed cardiac ischaemic times.215,219 AV block is lesscommon and is probably related to inadequate preservationof the donor heart.216,219

Following standard orthotopic heart transplantation,chronotropic incompetence is inevitable because of theloss of autonomic control. The heart rate response to exer-cise is characterized by a delayed onset, a reduced rate ofrise, and a lower maximal rate at peak exercise. Following

exercise, the heart rate increases further and then slowsdown gradually over time. The chronotropic responseimproves after the third week and remains unchangedafter 6 months, probably as a result of the inadequate inner-vation of the donor sinus node.220

Sinus node and AV node function, however, improve duringthe first few weeks after transplantation.217 Therefore,delaying pacemaker implantation will allow spontaneousrecovery of the sinus node and more appropriate patientselection.

Since there are no established criteria to identify patientswho may need a pacemaker, the optimal timing for perma-nent pacemaker implantation after transplantation isunclear. There is expert consensus that patients in whom

bradycardia persists after the third post-operative week,despite treatment with theophylline, require permanentpacemaker implantation. Pacing restores the chronotropic

Table 1.6.1 Recommendations for cardiac pacing after cardiactransplantation

Clinical indication Class Level of evidence

Symptomatic bradyarrhythmias due tosinus node dysfunction or

atrioventricular block 3 weeks aftertransplantation

Class I C

Chronotropic incompetence impedingthe quality of life late in thepost-transplant period

Class IIa C

Symptomatic bradyarrhythmiasbetween the first week and thirdweek after transplantation

Class IIb C

1. Asymptomatic bradyarrhythmiasand tolerated chronotropicincompetence

Class III C

2. Monitoring of cardiac rejectionalone

3. Bradyarrhythmias during the firstweek of transplantation

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competence and improves exercise capacity. Since the pres-ervation of AV synchrony results in an increased cardiacoutput, a DDDR mode with minimized ventricular pacing,or AAIR in the case of intact AV nodal conduction, is rec-ommended.219 Pacing recommendations after cardiac trans-plantation are summarized in Table 1.6.1.

2. Pacing for specific conditions2.1. Hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy is a genetically transmittedheart disease characterized by ventricular hypertrophy andmyofibrillar disarray. In about 25% of patients with familialhypertrophic cardiomyopathy, asymmetrical interventricu-lar septal hypertrophy leads to a dynamically variablepressure gradient between the apical LV and the outflowtract (LVOT).221 The narrowing of the outflow tract iscaused both by protrusion of the hypertrophied septumand by the systolic anterior motion of the mitral valvetoward the asymmetrically hypertrophied interventricularseptum. Mitral valve regurgitation is frequent. Early acutepacing studies indicated that right ventricular pacing couldreduce the LVOT gradient by 30%.222224

2.1.1. The rationale for short atrioventricular delay DDDpacing in hypertrophic obstructive cardiomyopathyPre-excitation of the right ventricular apex changes the ven-tricular contraction pattern, creating regional dyssynchrony(desynchronization). The altered LV activation pattern withlate activation of the basal part of the septum anddecreased LV contractility225227 increases the LV systolicdiameter and reduces the systolic anterior motion of themitral valve which as a net effect leads to a lowering ofthe LVOT gradient. Similar effects have also been shown in

patients with symmetric hypertensive hypertrophy anddistal cavity obliteration.227 Pre-excitation of the right ven-tricular apex is achieved by short AV delay DDD pacing. Theatria are sensed and trigger right ventricular pacing ahead ofspontaneous AV conduction. In addition to an altered ventri-cular contraction pattern, pacing results in redistributionof wall stress, probably causing modification of coronaryblood flow.228230 In the absence of mitral valve disease,DDD pacing reduces mitral incompetence,231 which in turncan be expected to help maintain the atrial contributionto ventricular filling. These beneficial effects of pacing canbe counteracted by potentially negative effects of shortAV delay DDD pacing, since pacing may raise left atrial

pressure

232,233

while simultaneously reducing filling andassociated pressures in the LV.227 Thus, the benefits of low-ering LVOT gradient and an increase in end-systolic volumeby 45% might be counterbalanced by a reduction in ventri-cular relaxation as a result of pacing.234,235 One studysuggests that the negative effect on diastolic functionoccurs mainly in patients with no previous diastolic dysfunc-tion.236 In contrast, in those with more severe diastolic dys-function, DDD pacing causes no further deterioration indiastolic function.

After a year of pacing, the reduction in gradient is main-tained when pacing is discontinued, which suggests ven-tricular remodelling resulting from pacing.237,238 Thereis, however, no evidence that pacing reduces septal

thickening.

2.1.1.1. Clinical effects of short atrioventricular delay DDD

pacing in hypertrophic obstructive cardiomyopathy

Uncontrolled studies have indicated that short AV delay DDDpacing reduces the LVOT gradient and relieves severe symp-toms in patients with hypertrophic obstructive cardiomyopa-thy (HOCM).239241 One randomized crossover study of 83patients with an LVOT gradient of at least 30 mmHg at restdemonstrated that short AV delay DDD pacing reduced the

LVOT gradient, improved New York Heart Association(NYHA) functional class and relieved symptoms with sus-tained effects over 3 years.242,243 Exercise tolerance wasonly improved in subjects with a reduced baseline exerciseduration, in whom a 21% improvement was seen during theDDD pacing period.

These results were not supported by two smaller random-ized crossover studies.244,245 In one study of 54 patients withan LVOT gradient of at least 50 mmHg, after 3 months ofpacing, a benefit of pacing compared with controls couldonly be seen in patients aged over 65 years.244 In thisstudy, the LVOT gradient was significantly reduced alreadywithin 3 months, with a sustained effect over 12 months.

Symptomatic improvement, in terms of quality of life andfunctional class, was only seen after 12 months of DDDpacing. These results illustrate the lack of direct correlationbetween a reduction in LVOT gradient and symptomaticrelief. In addition, pacemaker implantation caused aplacebo effect that became apparent after 3 months ofpacing.246 However, the long-term results from the samestudy suggest that the treatment effect remains after ayear of treatment when the placebo effect can be expectedto have waned.243,247 One study suggests similar beneficialeffects from pacing in patients without a significant LVOTgradient at rest.248

Although there is clear evidence that some patients derivea benefit from pacing, there is to date no certain way to

predict the response. A reduction in LVOT gradient doesnot correlate with symptomatic improvement.242244 In oneretrospective study with 12 months follow-up, patientswith disturbed diastolic function were generally older andmore likely to derive benefit from pacing in terms of NYHAclass than those with normal diastolic function.236 Althoughthis observation is derived from a single study, it is substan-tiated by the subgroup analysis of another,244 indicating thatolder patients might derive a benefit from pacing.

2.1.2. Therapy delivery and programmingFactors of crucial importance for therapeutic results are the

position of the right ventricular lead in the right ventricularapex,249 the full right ventricular apical pre-excitation, andoptimal diastolic filling of the LV. Since diastolic function isdisturbed in HOCM, the AV delay is crucial to ensure a fullatrial contribution to ventricular filling. The optimal AVdelay is defined as the longest AV delay which results infull pacing-induced ventricular pre-excitation (wide QRS)without disturbing LV filling. The sensed AV delay needs tobe shorter than the PR interval to achieve ventricularpacing. In some HOCM patients with a very short inherentPR interval, AV nodal ablation as adjunct therapy canenable the programming of an optimal AV delay, maintainingdiastolic function and enhancing the therapeutic effect ofpacing.250,251 The upper rate limit should be programmed

higher than the fastest sinus rate achievable during exercise

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to ensure permanent ventricular pacing even during briskexercise.

2.1.3. Indications for pacing in hypertrophic

obstructive cardiomyopathyDDD pacing partially reduces the LVOT gradient andimproves NYHA class and quality of life in patients withHOCM, as evidenced by one randomized study with a3-year follow-up.242,243 However, compared with septalablation and myectomy, the improvement in LVOT gradientand symptoms is of lesser magnitude.252 The advantages ofpacing are the relative simplicity of the procedure com-pared with septal ablation or myectomy. The lack of large

randomized trials makes the indications for pacing contro-versial. Currently, there is no evidence to suggest thatpacing alters disease progress or reduces mortality. There-fore, DDD pacing can only be considered in patients withcontraindications for septal ablation or myectomy, orthose requiring pacing for bradycardia or with an indicationfor an ICD. Pacing may, therefore, be an option primarily inelderly patients with drug-refractory HOCM.242,243 Pacingrecommendations for HOCM are summarized in Table 2.1.1.

2.2. Sleep apnoea

The sleep apnoea/hypopnoea syndrome is a very common

respiratory disturbance affecting 4% of middle-aged menand 2% of women.253 It is defined as a total or partial inter-ruption of inspiratory airflow during sleep, leading to areduction in oxyhaemoglobin saturation and to sleep frag-mentation. The syndrome is classified as either central orobstructive. In the former type, the respiratory disturbanceis due to the interruption of diaphragm activity because ofdysfunction of the central regulation mechanisms for respir-atory control and is very common among patients with CHF.In the latter, the muscle tone in the upper airways is insuffi-cient to maintain their patency. Both types are associatedwith increased cardiovascular morbidity and mortality.254,255

The diagnosis of the syndrome is based on overnight poly-somnography, whereas the treatment of choice is the appli-

cation of continuous positive airway pressure.256

In a recently published study,257 it was found that atrialoverdrive pacing at a rate of 15 b.p.m. higher than themean nocturnal heart rate had a positive effect on sleepapnoea, reducing both obstructive and central apnoeic epi-sodes in patients who were already paced for conventionalindications. Most patients had predominantly central sleepapnoea, whereas in those with predominantly obstructivesleep apnoea, the percentage of episodes of central type

was high. These positive results, however, were not con-firmed by other studies that included patients with pureobstructive sleep apnoea.258262 Thus, more studies areneeded to clarify the possible effect of atrial pacing onsleep apnoea and to determine in which subgroups ofpatients this approach might be beneficial. Finally, cardiacresynchronization with atrio-biventricular pacing has beenfound to improve central sleep apnoea, sleep quality, andsymptomatic depression in patients with CHF and intraven-tricular asynchrony, mainly by improving the pump functionof the heart.263,264

3. Cardiac resynchronization therapy inpatients with heart failure

3.1. Introduction

The first descriptions of the short-term haemodynamiceffects of left or of simultaneous right and LV stimulationwere published over 35 years ago.265268 However, the clini-cal applications of the stimulation technique known as CRTbegan in 1994, when Cazeau et al.,269 in France, andBakker et al.,270 in the Netherlands, described the firstcases of atrio-biventricular pacemakers implanted inpatients with severe CHF and no conventional indicationfor cardiac pacing. This concept was mainly based on the

frequent observation of intraventricular conduction delaysin patients with chronic CHF, due to ventricular systolic dys-function. In such patients, a QRS duration 120 ms is pre-valent in 2550%, and left bundle branch block is found in1527%.271 In addition, AV dyssynchrony, as indicated by aprolonged PR interval on the surface ECG, is present in upto 35% of severe CHF patients.

3.1.1. Rationale of cardiac resynchronizationAV and intraventricular conduction delays both furtheraggravate LV dysfunction in patients with underlying cardio-myopathies. Notably, left bundle branch block alters thesequence of LV contraction, causing wall segments to con-

tract early or late, with redistribution of myocardial bloodflow, non-uniform regional myocardial metabolism, andchanges in regional molecular processes, such as calciumhandling and stress kinase proteins.272276 Intraventriculardyssynchrony partly favours mitral valve incompetence andshortening of LV filling. In addition to intraventricular con-duction, delays in AV timing also influence the mechanicalfunction of the four cardiac chambers, in which optimaltiming of the atrial systole is linked to an increase incardiac output and the duration of diastolic filling and adecrease of pre-systolic mitral regurgitation. Thus, dyssyn-chrony seems to represent a pathophysiological processthat directly depresses ventricular function, causes LV remo-delling and CHF, and as a consequence causes a higher risk of

morbidity and mortality.

Table 2.1.1 Recommendations for cardiac pacing inhypertrophic cardiomyopathy

Clinical Indication Class Level of evidence

None Class ISymptomatic bradycardia due to

beta-blockade when alternativetherapies are unacceptable

Class IIa C

Patients with drug refractoryhypertrophic cardiomyopathy withsignificant resting or provoked LVOTgradient240242 and contraindicationsfor septal ablation or myectomy

Class IIb A

1. Asymptomatic patients Class III C2. Symptomatic patients who do not have

LVOT obstruction

LVOT left ventricular outflow tract.

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compared with OPT alone. At the end of a mean follow-up of29 months, a 37% relative risk reduction in the compositeendpoint of death and hospitalization for major cardiovascu-lar events (P, 0.001) and 36% in the risk of death (absolute:10%,P, 0.002) were observed. The effect on mortality wasmainly due to a marked reduction in CHF-related deaths. Itis, however, noteworthy that the extension study294 showeda delayed but highly significant 46% reduction in the risk of

sudden death with CRT.Thus, one large, randomized trial289 with more than 2

years follow-up indicates that CRT-P significantly lowerstotal mortality, whereas two trials demonstrate a reductionin morbidity.

3.1.2.4. Impact of cardiac resynchronization therapy

on cardiac function and structure

Cardiac remodelling is now viewed as an important target inthe treatment of CHF. A positive relationship betweenreverse ventricular remodelling and outcome has beendemonstrated with drugs such as angiotensin-convertingenzyme-inhibitors, angiotensin-receptor blockers, and

beta-adrenergic blockers, with a parallel improvement inventricular geometry and function and reduction in morbid-ity and mortality. Results of several non-controlled studiesindicate that CRT reverses LV remodelling, decreases LV end-systolic and end-diastolic volumes, and increases LVEF.These benefits were attributed to CRT, since discontinuationof pacing resulted in loss of improvement in cardiac func-tion.295 A consistent finding in the randomized trialsdesigned with up to 6 months of follow-up has been up to15% absolute reduction in LV end-diastolic diameter and upto 6% increase in LVEF following CRT.293297 These effectswere significantly greater in patients with non-ischaemicthan in those with ischaemic heart disease.295,297

Finally, the reverse remodelling process was sustained.In the CARE-HF study, the mean reduction in LV end-systolicvolume increased from 18.2% after 3 months to 26% after18 months of CRT. Similarly, mean LVEF increased from3.7% at 3 months to 6.9% at 18 months.289 These obser-vations provide consistent evidence of a large, progressive,and sustained reverse remodelling effect conferred by CRT.

3.1.3. Cost-effectiveness issuesExtensive cost-effectiveness analyses were done in theCOMPANION298 and CARE-HF299 studies. CRT was associatedwith increased total costs when compared with standardmedical treatment. Over a mean follow-up of 29.6 months

in CARE-HF,

299

the meanE

4316 overcost was mainly attribu-table to the device itself, with an estimated cost of E5825.The mean incremental cost-effectiveness ratio per lifeyear gained was E29 400299 and $28 100298 with CRT-Pand $46 700 with CRT-ICD.298 Extending the analysis toa patient life perspective, the mean incremental costgained per quality-adjusted life year (QALY) wasE19 319299 and $19 600298 for CRT-P, whereas it was morethan twice as high ($43 000) for CRT-ICD.298 These datasuggest that the clinical benefits of CRT are economicallyviable and can be achieved at a reasonable cost in mostEuropean countries. As cost-effectiveness of CRT-ICDcompared with CRT-P is age-sensitive, expected longevityshould help determine whether to use CRT-P or CRT-ICD in

the individual patient.300

3.1.4. Unresolved issues3.1.4.1. Patient selection: electrical or electromechanical

dyssynchrony criteria to select patients for cardiac

resynchronization therapy?

The response rate to CRT is limited to 6070% of patients andso there is a need for optimizing individual therapy deliveryand for developing selection criteria for CRT.271 Nonethe-less, the evidence for a clinical benefit from CRT is

derived from randomized studies using QRS 120 ms as amarker of ventricular dyssynchrony. Consequently, there iscurrently no evidence that CRT is indicated in CHF patientswith QRS ,120 ms. Electrical dyssynchrony does not alwaysaccompany mechanical dyssynchrony.271 Conversely, mech-anical ventricular dyssynchrony is not always linked to elec-trical dyssynchrony. For example, signs of intraventriculardyssynchrony have been reported by imaging techniques ina subset of patients with LV systolic dysfunction and a QRS,120 ms.301304 The mean QRS duration of heart failurepatients enrolled in these studies ranged from 110 to120 ms. In spite of positive results from observationalstudies of the benefit from CRT using mechanical dyssyn-

chrony criteria to select patients,

304,305

the real value ofthe mechanical dyssynchrony criteria for patient selectionremains to be determined in randomized studies. That isparticularly true for the so-called narrow QRS (,120 ms)patients.306308

3.1.4.2. Patients with atrial fibrillation

The randomized studies of CRT to date have been almostexclusively restricted to patients in sinus rhythm. The preva-lence of AF in patients with moderate-to-severe CHF,however, varies between 25 and 50%.309 This high preva-lence contrasts with the low percentage (2%) of patientswith AF enrolled in randomized trials of CRT. Therefore,we have little knowledge of the clinical value of CRT in

this population. The reasons for this lack of informationare various. Patients suffering from CHF, AF, and ventriculardyssynchrony are typically older, have a higher prevalenceof associated illnesses, and a worse prognosis than patientsin sinus rhythm.310 On the other hand, enabling incessantand complete ventricular capture may be inconvenient forthe patient, since this often requires the prior creation ofcomplete heart block by radiofrequency ablation of the AVjunction. Finally, outcomes are more difficult to measure,since both heart rate control and CRT may contribute tothe observed changes in clinical status. Thus far, a singlesmall controlled study (MUSTIC-AF) has yielded negativeresults in the intention-to-treat analysis, whereas the per-

protocol analysis showed a marginally significant functionalimprovement conferred by CRT.311 However, the results ofa recent large prospective observational study312 clearlydemonstrated that, over a long-term follow-up, combiningCRT with AV junction ablation (thus obtaining 100% effec-tive biventricular stimulation) conferred marked improve-ments in LV function and exercise capacity (comparablewith those achieved in patients with sinus rhythm). In con-trast, AF patients treated with CRT without AV junctionablation, in whom rate control was achieved by means ofnegative chronotropic drugs, performed very poorly. Twosmall trials, the OPSITE and PAVE trials, primarily focusedon patients with fast drug-refractory AF314,315 treatedwith AV junction ablation combined with different pacing

modes. Only a subset of patients in both trials had LV

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