central clinical research issues in electrophysiology: report of the naspe committee

526 April 2001, Part I PACE, Vol. 24

IntroductionThe purpose of this article was to define the

central clinical research questions in electrophys-iology as a vehicle to help in setting a researchagenda. The emphasis is on framing the questionsand some of the proposed approaches to address-ing them rather than on an exhaustive review ofthe various topics.

Sudden Cardiac DeathPopulations Studied

Sudden cardiac death (SCD) occurs in about400,000 people in North America each year,1,2

most frequently as the result of a ventricular tach-yarrhythmia. The implantable cardioverter defib-rillator (ICD) is highly effective in reverting suchrhythms to normal. Clinical trials have demon-strated that the ICD is superior to medication inprolonging the lives of individuals with a historyof prior, or inducible, sustained ventricular ar-rhythmia.3–5 However, most episodes of SCD oc-cur in the much larger at risk population that hasnot experienced a prior sustained ventriculartachyarrhythmia.6,7 A central clinical question ishow to identify individuals without a prior symp-tomatic ventricular tachyarrhythmia whose sur-vival can be prolonged by ICD implantation orother therapies.

Risk Factors

Certain cardiovascular conditions identify in-dividuals at risk for SCD. The two factors that arenumerically the most important are reduced leftventricular function and coronary artery dis-ease.8–11 Clearly, there is considerable overlap be-

NASPE POLICY STATEMENT

Central Clinical Research Issues inElectrophysiology: Report of the NASPECommitteeMICHAEL J. DOMANSKI,* DOUGLAS P. ZIPES,† DAVID G. BENDITT,‡ A. JOHN CAMM,§ DEREK V. EXNER,\ MICHAEL D. EZEKOWITZ,AH. LEON GREENE,** MICHAEL D. LESH,†† JOHN M. MILLER,‡‡ CRAIG M. PRATT,§§ SANJEEV SAKSENA,\\ MELVIN M. SCHEINMAN,AA

BRAMAH N. SINGH,*** CYNTHIA M. TRACY,††† and ALBERT L. WALDO‡‡‡From the *Clinical Trials Group, The National Heart, Lung, and Blood Institute, Bethesda,Maryland, †Division of Cardiology and Krannert Institute of Cardiology, Indiana UniversitySchool of Medicine, Indianapolis, Indiana, ‡Cardiac Arrhythmia Center, University of MinnesotaMedical School, Minneapolis, Minnesota, §Clinical Cardiology, University of London-St. George’sMedical School, London, England, \The National Heart, Lung, and Blood Institute, Division ofCardiology, Bethesda, Maryland, AYale University of School of Medicine, New Haven,Connecticut, **University of Washington, Seattle, Washington, ††University of California SanFrancisco Medical Center, San Francisco, California, ‡‡Krannert Institute of Cardiology,Indianapolis, Indiana, §§Baylor College of Medicine, Houston, Texas, \\Robert Wood JohnsonSchool of Medicine, New Brunswick, New Jersey, AAUniversity of California San FranciscoMedical School, San Francisco, California, ***University of California Los Angeles School ofMedicine, Los Angeles, California, †††Georgetown University, Washington, DC, ‡‡‡Case WesternReserve University School of Medicine, Cleveland, Ohio

DOMANSKI, M.J., ET AL.: Central Clinical Research Issues in Electrophysiology: Report of the NASPECommittee. This article contains the results of an attempt by appointed members of the North AmericanSociety of Pacing and Electrophysiology to define the research frontier in electrophysiology and suggestareas of study as an aid in setting the research agenda. (PACE 2001; 24[Pt. I]:526–534)

electrophysiology, arrhythmias, syncope, research

The views expressed in this article are not the views of the Na-tional Heart, Lung, and Blood Institute, National Institutes ofHealth, or the Department of Health and Human Services.

Address for reprints: Marilyn Bishop, R.N., NASPE, 6 Strath-more Rd., Natick, MA 01760-2499. Fax: (508) 647-0124.

Received November 28, 2000; accepted December 1, 2000.

Reprinted with permission fromJOURNAL OF PACING AND CLINICAL ELECTROPHYSIOLOGY , Volume 24, No. 4, Part 1, April 2001

Copyright © 2001 by Futura Publishing Company, Inc., Armonk, NY 10504-0418.

CENTRAL CLINICAL RESEARCH ISSUES IN ELECTROPHYSIOLOGY

PACE, Vol. 24 April 2001, Part I 527

tween these diagnoses because heart failure ismost frequently caused by coronary disease. Fol-lowing myocardial infarction (MI), left ventriculardysfunction is associated with a two- to ninefoldincreased risk of death depending upon the sever-ity of the dysfunction.8 The effectiveness of theICD in prolonging life in these patients is beingstudied in several trials (Table I). In the SecondMulticenter Automatic Defibrillator ImplantationTrial (MADIT-2), 1,200 post-MI patients withseverely reduced left ventricular ejection fraction(LVEF) (LVEF , 0.30) are being randomized toICD or to standard care. In the Sudden CardiacDeath in Heart Failure Trial (SCD-HeFT), 2,500heart failure patients with a LVEF , 0.35 are beingrandomized to placebo, ICD placement, or to treat-ment with amiodarone.

Risk Stratification

In addition advancing age, left ventriculardysfunction and the presence of coronary disease,a variety of electrophysiological abnormalitieshave been shown to be risk factors for SCD. Theyinclude frequent ventricular ectopy,12–15 in-ducibility of sustained monomorphic ventriculartachycardia (VT),16 an abnormal signal-averagedelectrocardiogram (ECG),17,18 increased QT dis-persion,19–24 depressed baroreceptor sensitiv-ity,25–27 reduced heart rate variability,28,29 and Twave alternans.30 It is essential to understand theutility of these risk factors in identifying at risk pa-tients who are likely to benefit from interventionand also to avoid unnecessary treatment of pa-tients who will not suffer a cardiac arrest. To dothis, the following research is suggested:

1. Prospective evaluation of the predictivevalue of risk stratification markers describedabove in patients with coronary artery disease andin patients with heart failure. While some infor-mation is already available, ongoing trials (Table I)provide excellent vehicles for accomplishing thisgoal.

2. Observational cohort studies such as thosein well-defined populations in which current andfuture risk stratification tools can be compared in-dividually and in combination.

3. Development of practical approaches to di-agnosing subclinical disease that will permit iden-tification of at risk individuals in the general pop-ulation.

4. Studies in whole organ preparations as-sessing the underlying subcellular, cellular, andtissue mechanisms of ventricular arrhythmias toprovide a basis for developing improved prognos-tic markers and therapies.

Antiarrhythmic Drug Therapy of VentricularTachyarrhythmias

Ventricular DysfunctionClinical trials demonstrating the superiority

of the ICD compared to antiarrhythmic drugs inSCD prevention, combined with the proarrhyth-mic potential of antiarrhythmic drugs, have had achilling effect on the stand-alone use of antiar-rhythmic agents in SCD prevention. However, apost-hoc analysis from the Antiarrhythmic versusImplantable Defibrillators (AVID) trial, suggeststhat the effectiveness of the ICD relative to amio-

Table I.

Ongoing Device Trials

Trial Population Risk Stratification Tool Agent

SCD-HeFT (ongoing) All heart failure NYHA II–III & LVEF # 0.35 Amiodarone, ICD, placeboMADIT-2 (ongoing) Post-MI; heart failure NYHA I–III & LVEF # 0.30 ICD, controlDEFINITE (ongoing) Non-CAD heart NYHA I–III, LVEF # 0.35 & ICD, control

PVC or NSVTDINAMIT (ongoing) Recent MI LVEF # 0.35 & decreased ICD, control

heart rate variabilityBEST-1CD (ongoing) Recent MI LVEF # 0.35 & PVC or b-blocker/ICD,

decreased heart rate b-blocker/guidedvariability AAD, b-blocker

AAD 5 antiarrhythmic drug, BEST-ICD 5 Beta-blocker Strategy Plus Implantable Cardioverter-Defibrillator Trial; DEFINITE 5Defibrillators in Non-ischemic Cardiomyopathy Trial; DINAMIT 5 Defibrillators in Acute Myocardial Infarction Trial; CAD 5 coronaryartery disease; ICD 5 implantable cardioverter-defibrillator; LVEF 5 left ventricular ejection fraction; MADIT-2 5 Multicenter AutomaticDefibrillator Implantation Trial-2; MI 5 myocardial infarction; NYHA 5 New York Heart Association functional class; PVC 5 greater than10 premature ventricular contractions/hour; SCD-HeFT; 5 Sudden Cardiac Death in Heart Failure Trial Success, Failure andComplication Rates Reported for Radio-frequency Catheter Ablation. AV 5 atrio-ventricular; AVN 5 atrioventricular node; NR 5 notreported; WPW 5 Wolf Parkinson White.

DOMANSKI, ET AL.


darone may be modulated by the LVEF, and theadvantage of the ICD may be lost in patients witha LVEF . 0.35.31 These data should be regarded ashypothesis generating and need to be testedprospectively.

ICD ShocksPatients with an ICD often receive frequent

shocks that have been associated with a worseprognosis. An approach to achieving optimal drugtherapy to reduce recurrent shocks would be auseful advance.

Given the above, the following research issuggested:

1. Comparison of the effect of “best” medicaltherapy with ICD placement on SCD and totalmortality in patients with a history of VT or ven-tricular fibrillation and well-preserved ventricularfunction. A testable hypothesis might be that a b-blocker, amiodarone, or a combination of the twois just as effective as an ICD in patients with LVEF$ 0.35.

2. Clinical trials designed to investigate themost appropriate adjunctive drug therapy to pre-vent ventricular tachyarrhythmias in patients re-ceiving ICD therapy. Endpoints of such studieswould be total mortality, defibrillator shocks,and/or quality-of-life. Such studies would com-pare the combination of ICD and various drugcombinations.

Finally, a registry that examines outcomes inpatients with less well-established indications forICD implantation, including relatives of patientswho have died suddenly and patients with hyper-trophic cardiomyopathy, long QT, arrhythmogenicright ventricular dysplasia, and other syndromeswould be useful in gaining an understanding of therole of the ICD in these patients.

Catheter AblationCatheter ablation has been applied exten-

sively to treat supraventricular tachyarrhythmiasand, indeed, has become the treatment of choicefor a number of them. Ablation of VT is less welldeveloped, except for certain patients with struc-turally normal hearts and well-defined sites of ori-gin, such as right ventricular outflow tract VT.

Supraventricular ArrhythmiasCatheter ablation is used routinely to treat

atrioventricular nodal (AVN) reentrant tachycar-dia, accessory bypass tract tachycardia, and in ab-lation of the AVN with pacer implantation for ven-tricular rate control of atrial fibrillation. Inaddition, atrial flutter and atrial tachycardia arealso frequently treated with catheter ablation.Table II presents the success and complicationrates compiled for each of these procedures.

Much of the advance that will occur incatheter ablation of the supraventricular tach-yarrhythmias will be related to new mapping tech-niques and new catheter and electrode technol-ogy. Precise characterization of clinical outcomesis important in optimizing treatment. The multi-tude of procedural and clinical issues and ques-tions that will arise with the introduction of eachnew device and technique lend themselves toevaluation by means of a carefully designed reg-istry. To be effective, such a registry needs to havea number of properties and should involve highlyexperienced centers that report consecutive casesaccording to a common format. The data shouldreside at a coordinating center that has the datamanagement and statistical support to properlyarchive and analyze the data. Examples of ques-tions that should be addressed are:

1. What are the true rates of success and com-plications for ablation of the various supraventric-ular arrhythmias?

Table II.

Success, Failure, and Complication Rates Reported for Radiofrequency Catheter Ablation

Arrhythmia Success Significant InadvertentSubstrate Rate Complications Complete

WPW Syndrome 80%–90% 1.8% 2%–5%*Slow Pathway (AVN modification) 97% 0.7% 0%–8%**Atrial flutter 72% 0.7% NRAV junction ablation 97% 3.7% NRAtrial tachycardia 71% 1.7% NR

* This is only for posteroseptal and anteroseptal pathways. This compilation is not associated with nonseptalpathways.** This reflects the incidence in studies that include only slow pathway ablation or both slow and fast pathwayablation for AV node reentry. (Kay, 1993; Scheinman, 1995: Wu, 1992; Jackman 1992, Jazayeri 1992). WPW =Wolff-Parkinson-White; AVN = adrioventricular nodal; AV = atrioventricular; NR = not reported.



2. How does success vary with type of hospi-tal: teaching, community, university, etc.?

3. What is the minimum number of proce-dures that an operator and a laboratory should per-form each year to remain proficient?

4. Are procedure time and radiation exposurerelated to patient volume?

5. What are the success and complicationrates for a particular approach?

6. Are there procedural factors that contributeto procedural success, like the use of heparin in aparticular procedure?

These are only examples. A registry wouldcharacterize the safety, efficacy, and cost-effective-ness of procedures and devices and provide the ba-sis for a variety of practice guidelines.

Ventricular Arrhythmias

The role of catheter ablation in the treatmentof VT is less well clarified, with certain exceptions,than in the treatment of the supraventricular ar-rhythmias. The reasons for this become clear withdiscussion of the various types of VT.

Post-MI VTThis category accounts for most of the sponta-

neous episodes of VT. The appropriate endpointsfor ablation procedures remain to be elucidated.Concern exists that the ablation procedure may notdefine and adequately treat all current and poten-tial (future) arrhythmogenic substrate. As a result,it is unclear under what circumstances, if any, theablation procedure obviates the need for an ICD.Further, it is not clear that even the successful ab-lation of a VT focus protects the patients from de-veloping ventricular fibrillation or VT originatingfrom a different focus. Also, the ICD is easily andsafely placed and functions with great effective-ness. As a result, a role for ablation in the post-MIpatient remains to be delineated, but may provemost useful as an adjunct to the ICD to reduce thenumber of episodes of VT that require ICD inter-vention. The exploratory nature of the data and thefact that there are relatively few cases at any onecenter make a registry format attractive for datagathering.

Cardiomyopathic VTVT in patients with nonischemic cardiomy-

opathy is difficult to study because of the relativeinfrequency of inducible, sustained, hemodynami-cally tolerated VT and the presumed heterogeneityof substrate. Bundle branch reentry is importantand easily ablatable in these patients32 but otherventricular arrhythmias are often inducible follow-ing ablation of the right bundle branch. For the

nonbundle branch VTs, the ICD has generally beenthe treatment of choice. Sustained uniform VT isinfrequent in the setting of idiopathic dilated car-diomyopathy (but may be more frequent with cer-tain etiologies including Chagas’ disease, sarcoid,and arrythmogenic right ventricular dysplasia).

Among the questions to be answered aboutthese arrhythmias are: What is the true incidenceof bundle branch reentrant ventricular arrhyth-mia? Are ICDs needed after ablation of bundlebranch reentrant VT? Are pacemakers needed?Can a group of patients be identified that does notneed an ICD following ablation of these arrhyth-mias? Prospective study of cardiomyopathy pa-tients without VT is needed to determine thescope of the problem and the role of ablation.

VT in the Absence of Structural Heart Disease

These arrhythmias include such entities asright ventricular outflow tract VT, left ventricularseptal related VT, and smaller numbers of othertypes.33,34 These arrhythmias are infrequent andoften well tolerated even without treatment.

In summary, there are many questions aboutVT ablation that lend themselves to a carefully de-signed registry or prospective study.

Device Performance TrackingEach year more than 100,000 cardiac pace-

makers and 25,000 ICDs are implanted in patientswith serious arrhythmias. The population of theUnited States with implanted pacemakers now ex-ceeds 1 million and there are about 100,000 pa-tients with an ICD. These numbers will increase.Industry estimates suggest that there will be an ap-proximately 5% annual growth in pacemaker im-plants and a more than 10% increase in ICD im-plantations. The increase in ICD implantationswill be particularly dramatic if new indicationsfor prevention of SCD evolve from studies now inprogress such as SCD-HeFT and MADIT 2.

Increasing numbers of patients are receivingmore complex permanent pacemakers with dualchamber capacity. Pacing leads are being im-planted in the coronary venous circulation. Inser-tion and removal of such leads pose even moresignificant challenges and risks. The indicationsfor pacemakers and ICDs may broaden to includepatients with atrial fibrillation and/or congestiveheart failure, which would represent a massive in-crease in the number of patients with implants.

Experience suggests that device failures areinevitable, particularly given the increasing com-plexity of these devices. Implantable devices en-counter hardware, software, and lead componentmalfunction. Malfunction may occur in up to 3%of all devices. Between 1983 and 1988 the General

DOMANSKI, ET AL.


Accounting Office reported that there were 256device recalls involving cardiac pacemakers andheart valves. It is estimated that 500,000 pace-maker systems or components are currently on re-call or on advisories throughout the world. A vari-ety of components have failed and have causedfailure to pace or sense that can result in patientdeaths. In one recent example of lead failure (theAccufix 330–801 lead [Telectronics Pacing Sys-tems, Inc., Engelwood, CO, USA]), there were fourdeaths and nine thoracotomies associated withatrial J-lead removal in a prospective follow-up of2,589 patients. A new fracture or lead disruptionoccurred in up to 5.6%/year of patients followedfor 5 years. Over 42,000 of these leads were im-planted worldwide; over 21,000 in the UnitedStates alone. It should be noted that the originalestimate for lead fracture of the Accufix was0.017% of implants, while the actual fracture ratewas between 18% and 25% of implants.

Despite the increasing prevalence of im-planted devices and their increasing complexity,performance surveillance has been limited. Cur-rent postmarket surveillance efforts are limited inscope and sample sizes are small. Devices are of-ten monitored for only short periods after implant.Following this, device related problems are re-ported only on a voluntary basis. Industry esti-mates of device failures, which are based on vol-untary device returns or internally (within thecompany) gathered data, have proven to be unreli-able. No mechanism is in place to assess the long-term performance, failure modes, or the patientimpact of device failures.

Without a systematic approach to data collec-tion for monitoring safety and efficacy, the publichealth risk from such therapy can be neither esti-mated accurately nor minimized. A registry is pro-posed that would use consecutive cases from ex-perienced centers reporting according to acommon format to better understand clinical out-comes, individual device performance includingcomponent longevity, comparisons of device per-formance, indications for implantation, long-termcharacteristics of pacing, and defibrillationthresholds of various devices and electrodes, andquality control issues.

SyncopeSyncope is a common medical problem with

many potential causes and a high recurrence rate.There is strong evidence that syncope in patientswith underlying structural heart disease is associ-ated with an adverse prognosis. Nonetheless, sub-stantial questions about the epidemiology, naturalhistory, and treatment of syncope remain.

EpidemiologyA number of widely quoted, but relatively

old, reports suggest that syncope accounts for ap-proximately 3% of emergency room visits andfrom 1% to 6% of general hospital admissions inthe United States.35–37 The Framingham Study re-ported that at least one syncopal event occurred inapproximately 3% of men and 3.5% of women38

and that the prevalence increased with age. Addi-tionally, among patients who have experiencedsyncope, symptom recurrence was reported to oc-cur in about 30% of individuals.38,39 For the mostpart, current understanding of the frequency withwhich syncope occurs in the general populationand its effect on health care economics relies on afew small reports. Some recent data suggest thatsyncope may be more frequent than is currentlyrecognized and that syncope may present as“falls” in older people.40

Epidemiological questions include:

1. What is the frequency with which syncopealone is the principal reason for seeking medicalattention?

2. To what extent are presenting diagnoses,like falls and seizures, mistakenly made in the set-ting of syncope and what are the economic effectsof misdiagnosis? What are initial/presumptive di-agnoses?

3. How are syncope patients currently man-aged and what is the cost? Can guidelines be es-tablished for cost-efficient management?

4. What experimental and chronobiologicalfactors play a role in occurrence of a syncopalevent in a susceptible individual at a specifictime?

5. What are the risks of job related injury oraccident due to syncope recurrence for the variousdisease categories associated with syncope?

Diagnosis of the Causes of SyncopeAn important diagnostic dilemma is that the

causes of syncope are often multiple. For instance,in patients with aortic stenosis, syncope is not duesolely to a narrowed orifice restricting left ventric-ular output, but also to inappropriate reflex va-sodilation and/or primary cardiac arrhythmias.Similarly, syncope in association with certainbrady- and tachyarrhythmias depends, in part, onneural reflex factors, specifically the ability to ini-tiate vasoconstriction in response to the stress ofan arrhythmia.41,42 Thus, an otherwise hemody-namically “benign” arrhythmia can cause signifi-cant hypotension in a diabetic or in someone withotherwise subclinical dysautonomia.

palpitations to exercise intolerance and can con-tribute to cardiac decompensation. Its increasedfrequency in older patients and the aging of thepopulation make therapeutic advances particu-larly important.

Epidemiological Studies

Despite the long-standing recognition of theimportance of atrial fibrillation, a number of natu-ral history questions that are of therapeutic im-portance remain to be answered. Addressing thesequestions will be aided by recent technologicaladvances including the development of transtele-phonic monitors and pacemakers with extensivedata storage capability and implantable looprecorders. Further, much information can begained from data recorded by ICDs.

Important epidemiological questions thatneed to be addressed in the immediate future in-clude:

1. Characterizing the natural history of loneatrial fibrillation.

2. Defining the natural history and progres-sion of postoperative or post-MI atrial fibrillation.

3. Defining the risks and optimal timing ofdiscontinuation of anticoagulation in differentatrial fibrillation populations.

4. Defining the role of antiarrhythmic ther-apy versus rate control and anticoagulation ther-apy for the postoperative surgical patient.

Advances in Understanding PathophysiologyNovel and previously postulated mecha-

nisms of atrial fibrillation have been eluci-dated.54,55 These include a single focus firingrapidly, multiple wavelet reentry, multiple unsta-ble reentrant circuits, spiral waves, a single reen-trant circuit of short cycle length resulting in fib-rillatory conduction, and atrial remodelingaffecting the anatomic and physiological sub-strate of atrial fibrillation.

Needed research includes:

1. Understanding the distribution and popu-lation characteristics of focal, multiple wavelet ormultiple unstable reentrant circuits.

2. Understanding the evolution of atrial fib-rillation episodes produced by the different mech-anisms.

Diagnostic ModalitiesBetter approaches to mapping the activation

sequence of atrial fibrillation to provide informa-tion regarding mechanism and, potentially, for ab-



Little has been documented regarding the fre-quency with which comorbidities contribute to anoccurrence of syncope. Important questions in-clude:

1. What comorbidities are associated withsyncope in various age groups? What role do theyplay in increasing susceptibility? What are therisks associated with syncopal events?

2. What is the role played by medications inincreasing susceptibility to syncope?

3. What is the diagnostic use of electrophysi-ological testing in individuals with underlyingheart disease34,43–47 compared to patients withstructurally normal hearts.

4. The importance of electrophysiologicaltesting in patients with syncope and severe leftventricular dysfunction is a potentially fruitfularea for further study. Previous studies suggestthat these patients are at particularly high mortal-ity risk.39,43 Whether electrophysiological testingseparates patients who need an ICD from thosewho do not is not known.

5. Tilt table testing is much used in the diag-nosis of syncope and appears to have good sensi-tivity and specificity.48–53 The combination of tilttable testing with electrophysiological testing ap-pears to be particularly useful in the diagnosis ofsyncope patients. Clinical issues that are unre-solved and deserving of study include:

a. Establishing the relationship between find-ings obtained during either tilt table or elec-trophysiological testing and the actual causeof syncope in a given individual.b. Correlating the hemodynamic findings dur-ing tilt table testing and hemodynamic find-ings during spontaneous syncopal events todetermine if the technique is applicable fordirecting treatment strategy.c. Determining the role, if any, of various neu-rotransmitters in facilitating neurally medi-ated faints.d. Determining to what extent direct neuro-logical system recording (e.g., peripheralsympathetic nerve traffic, ambulatory elec-troencephalography can be of value in ad-dressing the pathophysiology of neurally me-diated faints or in assessing the cause ofsyncope of unknown origin.

Atrial FibrillationAtrial fibrillation is the most common chronic

cardiac arrhythmia and is an important risk factorfor stroke. Additionally, it can impact negativelyon lifestyle by causing symptoms ranging from

DOMANSKI, ET AL.


lation need to be developed. Also, better ap-proaches to predicting who is at risk for stroke areneeded. Suggested research includes:

1. Development of better approaches to map-ping activation sequence.

2. Identifying prethrombotic or thromboem-bolic risk markers.

Therapeutic Approaches

A number of studies are examining whetherrate control alone or rhythm control is more ap-propriate in patients with atrial fibrillation inwhom both strategies are feasible. These includethe Atrial Fibrillation Follow-up Investigation ofRhythm Management (AFFIRM) trial,56 Rate Con-trol versus Electrical Cardioversion (RACE), Phar-macological Intervention in Atrial Fibrillation(PIAF [rate control versus maintenance of sinusrhythm]), and a new Department of Veterans Af-fairs study examining the effectiveness of amio-darone in preventing recurrent atrial fibrillation(the Sotalol Amiodarone Fibrillation EfficacyTrial).

Important clinical research questions in-clude:

1. The role of early intervention to convertatrial fibrillation with the object of slowing or pre-venting progression to chronic atrial fibrillation(early in its natural history and early after the on-set of an episode).

2. Trials that compare the effect on stroke,death, quality-of-life and progression to chronicatrial fibrillation of drug versus implantable de-vice (atrial defibrillator, atrial pacing, or both).

3. Development of a national device registryto study the safety and effectiveness of new de-vices for treating atrial fibrillation.

4. Assessment, in a clinical trial, of early car-dioversion (within 48 hours) compared to late car-dioversion at 1 month with endpoints of sinusrhythm maintenance, mortality, stroke, and majorhemorrhage.

5. Assessing the role of outpatient drug man-agement of paroxysmal atrial fibrillation (i.e., pill-in-the-pocket approach) using type IC agents.

Pacing in CardiomyopathyHypertrophic Cardiomyopathy (HCM)

Pacing can reduce left ventricular outflowtract obstruction in patients with HCM57–59 anduncontrolled data suggest that symptoms may bereduced.57 However, there are few data regardingthe relative effectiveness of the various treatment

modalities. Needed research includes:

1. Randomized controlled trial(s) that com-pare the various means of reducing outflow tractobstruction: medication, surgical septal my-omyectomy, alcohol induced septal infarction,and pacing. The endpoints should be total mortal-ity, major morbidity, symptomatic status, andquality-of-life.

2. A registry of AVN ablation plus atrioven-tricular (AV) pacing should be established to col-lect prospective data in a large set of patients (.100). A controlled trial comparing pacing tech-niques in the relief of symptoms and changes inoutflow gradient and ventricular mass is needed.

Substudies of the trials suggested above, orsmall free-standing studies, that investigate thephysiological basis for improvement (if any) andthe use of other pacing modes such as biatrial syn-chronous DDD pacing and trichamber pacing withor without ICD placement in patients with con-centric hypertrophy are also needed.

Dilated Cardiomyopathy/Congestive HeartFailure

A number of studies suggest that pacing maybe useful in optimizing hemodynamics in heartfailure patients.60,61 Several mechanisms havebeen suggested.62 With proper timing of AV syn-chrony, it may be possible to reduce mitral regur-gitation, optimize the timing of filling of the leftatrium and left ventricle, and reestablish appro-priate heart rate and chronotropic competence.Patients who seem most likely to benefit are thosewith long AV intervals, wide QRS (especially withleft bundle branch morphology), diastolic mitralregurgitation, bradycardia and/or chronotropic in-competence. Study is necessary to determine themost appropriate AV timing of the pacemaker.Also, the question of which chambers and whatpacing sites should be paced to optimize hemody-namics remains open. Three chamber pacing(right and left atria and right ventricle; rightatrium, right ventricle, left ventricle) and fourchamber pacing show promise.63,64 Ongoing stud-ies in patients with left bundle branch block or in-traventricular conduction delay are examining therelative effectiveness of three chamber pacing ver-sus two chamber pacing and no active pacing.Comparison of these modalities with four cham-ber pacing is needed.

Biventricular pacing improves control of tim-ing of left atrial and left ventricular contractionand results in shorter QRS complex duration.65

This pacing mode increases cardiac output andimproves exercise tolerance.



Needed research includes:

1. A controlled trial of dual chamber pacingversus no pacing in a heart failure population thatcompares survival in patients with and withoutpacing.

2. A controlled trial of biventricular pacingversus no pacing or dual (left atrium and left ven-tricle) chamber pacing in heart failure patients.The functional consequences of each pacing

mode should be evaluated in the context of thesestudies.

Concluding RemarksThe discussion and recommendations con-

tained in this article represent the best attempt bythe committee to paint a picture of the researchfrontier in electrophysiology. It is hoped that itwill prove useful in defining the current state-of-the-art and research needs and opportunities.

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