Catheter Ablation Therapy forAtrial Fibrillation

Joseph E. Marine, Jun Dong, and Hugh Calkins

Since cases were first reported in 1994, catheterablation of atrial fibrillation has undergone rapiddevelopment and expansion. The procedure beganas an attempt to recreate the Maze III operationwith a catheter technique. Understanding thecontribution of the pulmonary veins to the initiationand maintenance of atrial fibrillation led to dramaticchanges in procedural technique. The segmentalostial and the circumferential approaches haveemerged as the 2 dominant methods. Effortscontinue in academic centers to better understandthe pathophysiology of the arrhythmia and tofurther refine the ablation procedure to improvepatient outcomes.n 2005 Published by Elsevier Inc.

A trial fibrillation (AF) remains the most

common arrhythmia treated by internists

and cardiologists, and medical management for

many patients is inadequate to control symp-

toms. Over the past 11 years, catheter ablationfor the treatment of AF has evolved from an

investigational procedure to one that is now

performed on thousands of patients annually in

many large medical centers throughout the

world. The growing acceptance of this procedure

has been brought about by a steadily increasing

number of reports showing safety and efficacy of

catheter ablation of AF targeting the pulmonaryveins (PVs) and posterior left atrium (LA). In

this article, we will review the development of

the ablation procedure, highlighting current

Progress in Cardiovascular Disease178

From the Johns Hopkins University School of Medicine,

Baltimore, MD.Address reprint requests to Hugh Calkins, MD, Johns

Hopkins Hospital, Carnegie 592, 600 N. Wolfe Street,

Baltimore, MD 21287-0409. E-mail: hcalkins@jhmi.edu0033-0620/$ - see front matter

n 2005 Published by Elsevier Inc.

doi:10.1016/j.pcad.2005.06.011

techniques, outcomes, and complications. We

will also discuss several unanswered questions inthis growing and important field.

Background and HistoricalConsiderations

The era of catheter ablation therapy for cardiacarrhythmias began in 1982 with 2 reports of DCablation of the atrioventricular (AV) junctionfor control of ventricular rate in patients withintractable supraventricular tachyarrhyth-mias.1,2 This technique was soon adapted totarget the arrhythmia substrate for treatment ofWolff-Parkinson-White syndrome, AV nodalreentry, and ventricular tachycardia.3-5 In thelate 1980s and early 1990s, radiofrequency (RF)energy replaced DC shocks as a source ofablative energy, allowing safer and more con-trolled lesion formation. This technical advanceled to a more widespread use of catheterablation for arrhythmias, with higher successrates and lower complication rates beingreported.6-9 Current success rates for ablationof most accessory pathways and AV nodalreentry exceed 95%.10

Concurrently with the development of cathe-

ter ablation techniques described previously,

Cox11 developed a series of techniques for the

surgical disruption of AF, first in an animalmodel, and then in series of patients. The final

iteration, the Maze III procedure, was based on a

model of AF in which maintenance of the

arrhythmia requires maintenance of a critical

number of circulating wavelets of reentry, each

of which requires a critical mass of atrial tissue to

sustain it.12 The concept behind the Maze III, in

which a series of complete incisions were madein the left and right atria, was that by dividing

the atria into small-enough electrically isolated

subsections, maintenance of AF could be pre-

vented regardless of the mode of initiation. In the

s, Vol 48, No 3 (November/December), 2005: pp 178-192

CATHETER ABLATION THERAPY FOR ATRIAL FIBRILLATION 179

course of their research, these investigators

found that the left atrial lesion set was largely

sufficient to prevent AF, whereas right atriallesions were required to prevent development of

atrial flutter. Isolation of the PVs and posterior

LA was a feature common to all successful

iterations of the procedure.

With the Maze III approach, Cox11 and Cox

et al13 have reported maintenance of sinus

rhythm in 95% of patients at long-term follow-

up with stroke rates of 0.1% per year. Fifteenpercent of patients required pacemakers, and 7%

lost left atrial transport function. Interestingly,

success rates appeared to be equivalent in

patients with and without structural heart disease

and in those with paroxysmal and persistent AF.

Although these success rates stand as a bench-

mark for success in the treatment of AF,

application of the Maze III operation has beenlimited by morbidity and risk associated with

sternotomy/thoracotomy and cardiopulmonary

bypass, as well as by limited adoption among

cardiothoracic surgeons.

Catheter Ablation for AF—LinearAblation Approach

The success of the Maze III procedure in the

early 1990s led some interventional cardiac

electrophysiologists to attempt to reproduce the

procedure with RF catheter lesions using a

transvenous approach. Schwartz et al14 reported

recreation of the Maze III lesion set in a small

series of patients using specially designed

sheaths and standard RF catheters. Althoughthe efficacy was modest, complication rates were

high, and procedure and fluoroscopy times were

exceedingly long, this report demonstrated a

proof of concept that led others to try to improve

the catheter-based approach.

In 1996, Haissaguerre et al15 reported tech-

nique and outcomes of linear catheter ablation

in 45 patients undergoing right and/or left atrialablation for paroxysmal AF. They found that

right atrial ablation (with 2 or more proce-

dures in 19 patients) led to rhythm control in

15 patients (33%), 9 of whom required antiar-

rhythmic drugs. Ten patients in whom right

atrial ablation was unsuccessful then underwent

left atrial ablation via transseptal approach,

leading to rhythm control in 6 patients (60%),

2 of whom remained on antiarrhythmic drugs.

Further refinement of linear catheter ablationtechnique by this group was reported in

1999.16 In this series of 44 patients with AF

(40 paroxysmal), all patients underwent a

series of ablation lesions using RF catheters

to create specific lesion sets in the right

(2 lines) and left (3-4 lines) atria. The right

atrial lesion sets consisted of an intercaval line

along the interatrial septum and a cavotricus-pid isthmus line to prevent atrial flutter. Left

atrial lesions were designed to connect the

4 PVs to each other and to the mitral annulus.

An additional line from right PVs to interatrial

septum was performed in 23 patients. Of note,

this series of patients required a mean of 2.7 F 1.3

procedures to complete the lesions and to

ablate postprocedure atrial flutters, which oc-curred in 31 patients and were generally

observed to be caused by incomplete lines of

block. Interestingly, 29 patients were observed

to have areas of focal electrical discharge

initiating AF and underwent attempted ablation

of these foci, 36 (97%) of 37 of which were

located in the PVs.

Of the 44 patients treated in this manner, 25(57%) achieved long-term maintenance of sinus

rhythm without antiarrhythmic drugs, and 27%

had improved rhythm control on antiarrhyth-

mic drugs. The investigators noted significant

complications in 9 patients, including pericar-

dial effusion, (5) pulmonary embolus, (1)

inferior myocardial infarction, (1) PV throm-

bosis, (1) and transient ischemic attack. (1)Although this report presented the best results

that have been achieved with a catheter-based

linear approach, the authors concluded that

safety, efficacy, and applicability needed to be

improved. Furthermore, in retrospect, it is

likely that ablation of initiating PV foci signif-

icantly improved their results compared with a

pure linear approach. Other groups attemptedmulticenter trials of linear ablation of AF using

novel multipolar ablation catheters; these trials

were terminated prematurely due to high

complication rates and poor efficacy.17 On the

basis of these observations and the rapid

advances in ablation of AF targeting initiating

focal triggers, catheter-based linear ablation

approach for AF has been largely abandoned.

Fig 2. Endocardial view of reconstructed magneticresonance image of the posterior LA showing theostia of the PVs and left atrial appendage as marked.Abbreviation: LAA indicates left atrial appendage.

MARINE, DONG, AND CALKINS180

Catheter Ablation for AF:Focal Approach

One important observation which came from

the work of Haissaguerre et al18 from their early

work in ablation of AF was the fact that some

patients with paroxysmal AF appear to have a

focal source of electrical activity triggeringsome or all paroxysms of AF. They published

a series of 3 patients with right atrial focal

triggers in 1994.18 The same group reported a

series of 9 patients in 1997; 3 had a focal source

in the right atrium, and 6 had foci at the ostium

of 1 of the PVs.19 Patients were young (mean

age, 38 F 7 years) and had structurally normal

hearts. All patients were successfully treatedwith a mean of 4 F 4 RF energy applications.

They published findings in a larger series of

45 patients in a landmark publication in 1998.20

Patients had a mean age of 54 F 11 years and

had frequent (often daily) paroxysms of drug-

refractory AF for a mean of 6 F 6 years. Most

patients (69%) had structurally normal hearts.

Patients also had at least 700 isolated prematureatrial ectopic beats on a 24-hour Holter moni-

toring. It is thus important to note that this was a

highly selected subpopulation of AF patients. All

patients underwent intracardiac mapping to

localize the source of the premature atrial

ectopic beats; 69 ectopic foci were found and

targeted for ablation. Remarkably, 65 foci (94%)

Fig 1. Reconstructed MR image showing posteriorview of the LA and the PVs as marked. Abbreviations:LSPV indicates left superior PV; LIPV, left inferior PV;RSPV, right superior PV; RIPV, right inferior PV.

originated within PVs, most within 2 to 4 cm of

the ostium. AF was initiated with a burst of rapid

firing from the foci and was abolished with RF

ablation at the site of origin. After a follow-up

period of 8 F 6 months, 28 patients (62%) werefree of AF off antiarrhythmic drugs, a substantial

effect given the frequency and long duration of

symptoms preceding the procedure. These find-

ings were soon replicated by other groups.21

The electrophysiological basis of these focal

sources appeared to be sleeves of left atrial

muscle investing the PVs, an anatomical obser-

vation that had been made decades ago.22 One ormore veins develop abnormal, paroxysmal, rapid

automaticity, triggering AF as a result. Despite

extensive research, the pathophysiology of this

process remains poorly understood. Magnetic

resonance imaging (MRI) studies from our

institution have shown that patients with AF

tended to have larger PV diameters, although

there was a significant overlap in size withasymptomatic control patients (Figs 1 and 2).

Variant anatomy was observed in 38% and was

seen equally in patients and controls.23,24

With further research in this area, it was also

observed that non-PV foci were an important

source of AF in some patients, although percen-

tages vary among different groups. Among the

sources identified are the vein of Marshall(a remnant of the fetal left superior vena cava

on the posterior left atrial wall), the coronary

CATHETER ABLATION THERAPY FOR ATRIAL FIBRILLATION 181

sinus, and the superior vena cava—all thoracic

veins.25,26 Other reported sources include the

left atrial posterior wall and right atrium.27 Morerecent reports have described AF triggered by

foci in the inferior vena cava and in a persistent

left superior vena cava.28,29 Investigators have

debated the frequency of these non-PV sources.

Another important observation made at this

time was the unique risks of ablation within the

PV—stenosis and occlusion. Robbins et al30

reported the occurrence of severe PV stenosisin 1998 in 2 patients after linear ablation in the

LA. With increasing use of focal ablation of PV

triggers, the problem of PV stenosis quickly

became recognized due to its serious sequelae,

including hemoptysis, pulmonary edema, and

pulmonary hypertension.31 One fatality was

reported in a patient after undergoing urgent

surgical intervention.32 Other attempted treat-ments have included pulmonary venous angio-

plasty and stenting, and resection of the

segments drained by the stenotic/occluded PV.33

Another problem with the focal approach to

PV ablation was the recognition that after

successful ablation, recurrence rates were high,

and remapping usually showed new foci in the

ablated vein or in other veins rather thanrecurrence of the original focus. In other words,

paroxysmal AF appears to be a field effect,

rendering patients susceptible to recurrent AF

from multiple foci.34 A final major limitation of

this approach is that it requires that atrial

premature beats triggering AF be observed

during the ablation procedure, limiting it to

patients with frequent spontaneous or inducibleatrial premature beats.20

Fig 3. Fluoroscopic image of the LA in the rightanterior oblique view demonstrating technique ofsegmental ostial PV ablation. Abbreviations: MAPindicates the multipolar circular mapping catheterpositioned at the ostium of the right superior PV; ABL,RF ablation catheter; CS, multipolar catheter posi-tioned in the coronary sinus.

PV Ablation for AF: SegmentalOstial Approach

Recognition of these major limitations of focal

ablation led to development of PV isolation

technique. Recognizing that PV musculature

conducts to left atrial musculature by discreteconnections allowed investigators to target those

connections using multipolar catheters shaped

into rings or baskets.35,36 After placement of

diagnostic EP catheters in the coronary sinus and

sometimes other sites, 2 long sheaths are placed

across the interatrial septum with a double

transseptal technique. After defining PV anatomy

with contrast venography, a circular mapping

catheter is placed at the ostium of the targeted

PV (Fig 3). Ablation is performed with a separateroving catheter through the second transseptal

sheath at the site of earliest activation sequen-

tially until PV electrical activity disappears or

becomes dissociated from LA activity (Fig 4).37

Using this strategy, between 20% and 60% of the

PV circumference is targeted for ablation. It was

found that by ablating at or just outside the PV

os, the incidence of PV stenosis could be reducedsignificantly. PV isolation has the additional

advantage of simultaneously treating all trigger-

ing foci within the vein, thereby obviating the

need to elicit and map those foci individually.

Marchlinski et al38 compared their experience

with focal vs segmental ostial isolation for

treatment of AF in 107 patients and found

freedom from AF at 1 year in 80% of patientstreated with PV isolation vs 45% of patients

treated with focal ablation. For the same reason,

investigators were soon led to attempt to isolate

as many PVs as possible at the initial ablation

session. Comparative case series ultimately dem-

onstrated that empiric 4-vein isolation led to

superior outcomes over isolating fewer veins.39

Using this approach, EP centers began report-ing success rates of 60% to 80% for patients with

Fig 4. Intracardiac electrograms demonstrating effect of ablation on the PV potentials (PVPs), indicated by thearrows, during coronary sinus pacing. Note the progressive prolongation of conduction time from the pacingstimulus to the PVPs during the tracing, with complete loss of PVPs in the last 2 paced beats.

MARINE, DONG, AND CALKINS182

paroxysmal AF with medium-term follow-up.40

Recurrences were found generally to result from

reconnection of previously isolated veins or

ectopy in PVs not targeted at the initial proce-

dure.41 A minority of recurrences have been

shown to be due to non-PV triggers.

The experience with this approach at Johns

Hopkins Hospital was recently reported for

a consecutive series of 75 patients who under-went segmental ablation for the treatment of

paroxysmal (n = 42) and persistent or permanent

(n = 33) AF.42 The overall efficacy, defined as the

absence of symptomatic AF recurrence without

antiarrhythmic drugs, at a mean follow-up of

10 months was 52%.The efficacy was better for

paroxysmal in comparison to persistent or

permanent AF (76% vs 21%, respectively). Thecomplication rate was 11% including significant

PV stenosis, stroke, cardiac tamponade, and

mitral valve injury.

Table 1 summarizes the outcomes of 8 case

series or trials which have reported on the safety

and efficacy of segmental ostial ablation for the

treatment of AF.36,40,42-47 Medium-term successwas achieved in 196 (70%) of 280 patients with

paroxysmal AF and 21 (30%) of 70 patients with

persistent/permanent AF. The overall major

complication rate was 6.3%, including stroke

(0.7%), pericardial tamponade (1.2%), and sig-

nificant PV stenosis (4.3%).

One important limitation of available data on

segmental ostial PV ablation for AF is the paucityof long-term follow-up data for both efficacy and

late complications. Mean follow-up of the

reported studies ranged from 4 to 21 months.

Patients may have recurrence later than this due

to reconnection of previously isolated veins,

emergence of non-PV triggers, and progressive

alteration of left atrial substrate. It is thus difficult

to know when a patient may be consideredbcuredQ of AF. A second limitation is that the

definition of success in most of these trials was

the elimination of bsymptomaticQ AF. It has been

recognized that some AF patients have asymp-

tomatic episodes, even those patients who are

highly symptomatic with some episodes of AF.48

Table 1. Summary of Clinical Studies of Segmental PV Ablation

Study YearFollow-up(mo)

Success Complications

OverallParoxysmalAF

Persistent orPermanentAF

PVStenosis(N50%) Stroke

CardiacTamponade

MitralValveInjury

Haissaguerre et al36 2000 4 F 5 51/70 (73) 51/70 (73) – 0 0 0 0Oral et al40 2002 5 F 3 44/70 (63) 41/58 (71) 3/12 (25) 0 1 (1.4) 0 0Deisenhofer et al43T 2003 8 F 4 38/75 (51) N/A N/A 6 (8) 0 4 (53) 0Marrouche et al44y 2003 14 F 5 271/315 (86) N/A N/A 22 (7) 2 (0.6) 0 0Arentz et al45 2003 12 34/55 (62) 26/37 (70) 8/18 (44) 1 (1.8) 0 1 (1.8) 0Oral et al47 2003 6 27/40 (67) 27/40 (67) – 0 0 0 0Mansour et al46 2004 21 F 5 22/40 (55) 19/33 (58) 3/7 (43) 0 0 2 (5) 0Vasamreddy et al42 2004 11 F 8 39/75 (52) 32/42 (76) 7/33 (21) 3 (4) 2 (2.6) 2 (2.6) 1 (1.3)Overall – – 526/740 (71) 196/280 (70) 21/70 (30) 32 (4.3) 5 (0.7) 9 (1.2) 1 (0.1)

Values are given as n (%); success was defined as free of AF recurrence without antiarrhythmic drugs.TSeven-day Holter monitoring was used to screen AF recurrence.yIntracardiac echocardiography was used to monitor ablation in 259 patients.

CATHETER ABLATION THERAPY FOR ATRIAL FIBRILLATION 183

In summary, the technique of segmental ostial

PV isolation represents an important advance in

catheter treatment of AF over the focal ap-

proach. Studies have shown good medium-term

success for patients with paroxysmal AF butgenerally poor results for persistent and perma-

nent AF. It remains the preferred approach to

paroxysmal AF in some EP centers, although

most have moved toward techniques to modify

left atrial substrate, as will be described in the

following sections.

Fig 5. Electroanatomical map of the LA and PVsdemonstrating CPVA lesion set (red points). Per-spective is similar to the MR image in Fig 1. Notethat ablation is performed well outside the PVs. Inthis example, a roof line and mitral isthmus linewere performed.

PV Ablation for AF: CircumferentialApproach

Concurrently with the development of the

segmental approach to PV isolation, Pappone et

al49 and Pappone and Santinelli50 working in

Milan developed the circumferential approach

using electroanatomical mapping. After place-

ment of 1 or more diagnostic electro-physiologycatheters, a single transseptal puncture is per-

formed, and a long sheath is placed in the

LA. Using a magnetic-based electroanatomical

mapping system (CARTO, Biosense-Webster

Diamond Bar, CA), an anatomical shell is con-

structed with the mapping/ablation catheter,

including the PVs. RF ablation is then performed

circumferentially around each vein with theend point of ablation being the absence or

marked reduction (80%) in the amplitude of elec-

trical signals within the encircling lesions. In

cases where the inferior and superior veins were

closely spaced or shared a common ostium, a

single large circumferential RF lesion set was

performed (Fig 5). Despite lack of evidence

showing that PVs treated in this way were

electrically isolated from the LA, this group

began reporting results for paroxysmal AF whichwere just as good or better than those working

with ostial segmental approach.51 Furthermore,

patients with persistent/permanent AF treated

with the Pappone approach achieved freedom

from AF nearly as good as those with paroxysmal

AF and far better than reports of patients treated

with segmental PV isolation.

In 2001, Pappone et al52 reported results of thisprocedure in 251 consecutive patients with drug-

refractory AF (179 with paroxysmal AF and 72

MARINE, DONG, AND CALKINS184

with persistent/permanent AF). Procedure time

was 148 F 26 minutes and shortened significant-

ly with operator experience. A mean of 92 F 16RF lesions were made per patient, with a mean

ablation time of 52 F 12 minutes, representing a

significant increase compared with ostial seg-

mental ablation. Electroanatomical mapping im-

mediately after ablation showed that an estimated

23% F 9% of the entire left atrial surface area

was transformed to a low-voltage or electrically

silent state. After a mean follow-up period of10.4 F 4.5 months, 85% of patients with parox-

ysmal AF and 68% of patients with permanent AF

were free of symptomatic AF. Despite the increase

in ablation time and large area of the LA ablated,

major complications were limited to 2 patients

with pericardial tamponade (0.8%), with no PV

stenosis or thromboembolism.

The experience of Johns Hopkins Hospitalwith circumferential ablation was recently

reported in a consecutive series of 70 patients

who underwent circumferential ablation for the

treatment of paroxysmal (n = 21) or persistent/

permanent (n = 49) AF.53 The overall efficacy, at

a mean follow-up of 6 months was 56%. The

efficacy was similar for paroxysmal and persis-

tent/permanent AF (62% vs 53%, respectively),and the complication rate was 5.6%.

These results are consistent with those re-

ported by other centers. Table 2 summarizes the

outcomes of 6 case series or trials which have

reported on the safety and efficacy of circum-

ferential ablation for treatment AF.46,47,52-55

Long-term success was achieved in 290 (74%)

Table 2. Summary of Clin

Study YearFollow-up(mo)

Success

OverallParoxysmAF

Pappone et al52 2001 10 F 5 188/251 (75) 148/179 (Oral et al47 2003 6 35/40 (88) 35/40 (Mansour et al46 2004 11 F 3 25/40 (63) 21/32 (Kottkamp et al54T 2004 12 37/100 (37) 34/80 (Ouyang et al55y 2004 6 F 1 39/41 (95) 39/41 (Vasamreddy et al53 2004 6 F 3 39/70 (56) 13/21 (Overall – – 363/542 (67) 290/393 (

Values are given as n (%); success was defined as free of ATSeven-day Holter monitoring was used to screen AF recurreyTwo Lasso catheters were used to guide ablation to achieve

of 393 patients with paroxysmal AF and 73

(49%) of 149 patients with persistent/permanent

AF. The overall major complication rate was2.4%, including stroke (0.4%), pericardial tam-

ponade (0.7%), and PV stenosis (0.4%).

In 2003, Oral et al published prospective

randomized study comparing the segmental ostial

PV isolation approach with circumferential PV

ablation (CPVA) approach.47 In this study,

80 patients with symptomatic drug-refractory

paroxysmal AF were randomly assigned to the2 approaches. CPVA approach was found to be

more effective in prevention of symptomatic

recurrence of AF at 6-month follow-up (88% vs

67%). The only complication in this study was left

atrial flutter in a patient who underwent CPVA

approach. Although further studies are needed to

confirm these findings, the relative simplicity in

technique and reportedly equivalent or greaterefficacy have led many centers to adopt the

circumferential approach to PV ablation.86

PV Ablation for AF: HybridApproaches

The reported success of the circumferential

approach has raised several important questions

in the field of ablation for AF and has ledinvestigators to attempt modifications to the

standard circumferential lesion set, resulting in

hybrid approaches to AF ablation. The first

question is whether complete electrical isolation

of the PVs is necessary to achieve clinical

success. Several investigators have addressed

ical Studies of CPVA

Complications

alPersistent orPermanentAF

PVStenosis(N50%)

CardiacTamponade Stroke

LeftAtrialFlutter

83) 40/72 (56) 0 2 (0.8) 0 088) – 0 0 0 1 (2.5)66) 4/8 (50) 0 1 (2.5) 1 (2.5) 043) 3/20 (15) 0 0 0 4 (5)95) – 0 0 0 062) 26/49 (53) 2 (2.8) 1 (1.4) 1 (1.4) 074) 73/149 (49) 2 (0.4) 4 (0.7) 2 (0.4) 5 (0.9)

F recurrence without antiarrhythmic drugs.nce.PV isolation.

CATHETER ABLATION THERAPY FOR ATRIAL FIBRILLATION 185

this question and come to differing conclusions.

Cappato et al56 studied 43 AF patients with

serial electrophysiology studies and found ahigh rate (80%) of recurrent PV conduction

from previously disconnected veins; interesting-

ly, freedom from AF was no more likely in

those with recurrent conduction than those

without. Furthermore, 40% of patients who

had recurrence of PV conduction were free of

AF. In contrast, Gerstenfeld et al41 studied

34 patients with recurrent AF after initial PVisolation and, with careful PV mapping, found

that 86% of recurrent AF triggers came from

PVs which had either not been targeted for

initial ablation (32%) or had developed recur-

rent conduction (54%).

A recent report strongly suggests that achieve-

ment of complete PV isolation improves out-

come with the circumferential approach. Ouyanget al55 treated 41 patients with paroxysmal AF

with a modified circumferential ablation ap-

proach. In each patient, a single large extraostial

circumferential lesion set was placed around

inferior and superior PVs on each side, while a

circular mapping catheter was present in each of

the 2 ipsilateral veins. Ablation was continued

until complete electrical isolation was achievedin all 4 PVs. Ten patients had early recurrence,

and 9 underwent a second procedure—all

9 patients showed recurrent conduction from a

previously isolated PV and underwent reisola-

tion of that PV. At 6 F 1 months’ follow-up, 39

(95%) of 41 patients were free of AF without

antiarrhythmic drugs. Major complications were

limited to 1 patient with asymptomatic PVstenosis in a single PV. Although these results

are encouraging and suggest that the additional

procedural complexity of PV mapping is justi-

fied, further investigation is needed. In particu-

lar, it is unknown whether PV isolation adds to

success of circumferential ablation for persistent/

permanent AF.

A second important question concerns thesafety and efficacy of adding left atrial linear

lesions to the basic CPVA lesion set. The 2 linear

lesions most commonly added are a line con-

necting the right and left superior veins across

the superior aspect of the LA (so-called broof Qline) and a line connecting the left inferior PV to

the mitral valve annulus (so-called bmitral

isthmusQ line). These lesion sets are designed

to further modify electrical substrate to prevent

AF as well as to prevent left atrial flutters which

might be formed by the large circumferentiallines of block. Jais et al57 have shown that

achieving block with the mitral isthmus line in

particular is technically challenging and some-

times requires ablation deep within the coronary

sinus. Whether these additional lines improve

clinical success remains to be determined, but

many centers are adding these lesions in patients

with persistent/permanent AF or with inducibleAF or left atrial flutter after the standard

circumferential lesions are made.58

A third major question is how bsubstrate

modificationQ of the LA is achieved by PV

ablation, and whether modification of autonomic

innervation of the LA or prevention of rotor

formation plays a significant role in procedural

success. Pappone et al59 studied 297 patientsundergoing circumferential ablation for parox-

ysmal AF and found that 34% of them showed

evidence of cardiac vagal denervation during the

ablation procedure and in follow-up. They found

that ablation along the posterior LA in their

standard lesion set sometimes produced a vagal

reflex, resulting in sinus bradycardia and tran-

sient AV block. When ablation was continued atthese sites, loss of the reflex occurred, suggesting

vagal denervation, which was confirmed by

indices of heart rate variability on follow-

up Holter monitoring. Remarkably, 99% of

100 patients who achieved complete vagal

denervation were free of AF at 12 months vs

85% of the remaining patients ( P = .0002).

A recent article by Nademanee et al60 repre-sents a more fundamental challenge to current

concepts underlying catheter ablation of AF. This

group studied 121 patients with drug-refractory

paroxysmal (57 patients) and persistent/perma-

nent (64 patients) AF and used a novel approach

to mapping of AF substrate and performing

ablation. During AF in all patients (spontaneous

or induced), biatrial electroanatomical mappingwas performed. Areas of complex fractionated

electrical potentials were noted and tagged.

These sites, hypothesized to be pivot points for

reentrant wavelets, were targeted for ablation,

using a mean of 64 F 36 pulses. Sites were spread

over 9 areas of both atria and were not confined

to the PVs, which were not specifically targeted

for isolation. Using this approach, termination of

MARINE, DONG, AND CALKINS186

AF occurred during ablation in 91% of patients.

At 12-month follow-up, 70% of patients were

free of AF off antiarrhythmic drugs; with asecond procedure, success rate increased to 83%.

Complication rate was comparable to other

approaches and included 1 stroke, 2 pericardial

tamponades, and 1 complete AV block. This

novel approach, if confirmed by larger series and

with other centers, has the potential to alter both

our understanding of the mechanism of AF in

human beings and the current approach tocatheter ablation.

Risks and Benefits of CatheterAblation for AF

As with any other procedure in clinical medi-

cine, potential risks and benefits need to be

considered in deciding what to recommend for a

particular patient. With growing experience incatheter ablation, important information has

been revealed on both sides of the equation. In

addition to risks common to all catheter-based

cardiac procedures, several of these risks are

unique to or increased with ablation of AF.

The issue of PV stenosis has been raised

previously and appears to be markedly increased

by ablation within the ostium of the PV and withmultiple high-energy lesions around the circum-

ference of the ostium.31,61 Rates of significant PV

stenosis as high as 10% were seen with early

experience with focal PV ablation and have been

reduced to 0.6% with circumferential ablation

with some centers reporting no cases in large

series. Variation in incidence may depend on

how stenosis is measured and defined and howcarefully it is sought after the procedure. In a

series from our institution in which all patients

underwent MRI pulmonary venography before

and 6 weeks after ostial segmental ablation with

an irrigated-tip catheter, the incidence of mod-

erate or severe stenosis was 2.8%, and mild

narrowing was seen in 21% of targeted veins.23

However, no patient had symptoms or requiredtreatment, and therefore, none would have been

detected with a symptom-based follow-up imag-

ing strategy. Although the incidence is declining

with evolution of ablation technique, the pre-

vention of PV stenosis will remain an important

issue in the field, as it has been associated with

severe symptoms in some patients and has

proved difficult to treat. Furthermore, no proce-

dural technique has been proven to be entirely

free of this risk.Stroke, although infrequent, continues to be an

important issue. The Worldwide Survey on

Ablation of Atrial Fibrillation found 20 strokes

reported for 7154 left-sided AF ablation proce-

dures, an event rate of 0.25%, including

2 deaths.62 The rate of transient ischemic attack

was 0.66%. Potential sources of emboli include

thrombi adherent to catheters and sheaths,endocardial disruption from the ablation lesions,

thrombi or air passing through patent foramen

ovale or transseptal access, and air introduced

through transseptal sheaths. Careful attention to

anticoagulation and sheath management should

reduce risk, but the nature of the procedure with

prolonged left-sided catheterization and exten-

sive left atrial ablation in patients predisposed tostroke precludes eliminating it entirely. Whether

ablation with irrigated-tip catheters or cryoabla-

tion can reduce risk further remains to be

determined.63-65

Permanent diaphragmatic paralysis was re-

ported in 10 (0.11%) of 8745 cases in the

Worldwide Registry and probably relates to

ablation within the right superior PV or superiorvena cava and/or extensive linear ablation along

the lateral right atrial wall.62 Current PV ablation

techniques would not be expected to cause this

complication.

Left atrial tachycardias and flutters may be

considered either a form of procedural failure or

proarrhythmic complication. Gerstenfeld et al

found an incidence of 10 (2.9%) in 341 patientsundergoing segmental ostial PV isolation.66 In

contrast to previous reports, 8 of 10 of these

tachycardias were focal in origin. The CPVA

approach appears to be associated with a higher

risk of LA flutter and tachycardia. In a recent

trial, Pappone et al58 found an incidence of 10%

in 280 patients undergoing CPVA alone; this was

reduced to 3.9% in a randomized control groupundergoing linear lesions in addition to CPVA.

Between 70% and 80% of these organized

tachycardias were macroreentrant in each group.

Rate of recurrent AF was 13% to 14% in each

group. Other groups have raised concern that

addition of linear lesions, if incomplete, could

lead to an increased rather than decreased

incidence of this problem.

CATHETER ABLATION THERAPY FOR ATRIAL FIBRILLATION 187

An important newly recognized complication

of the circumferential ablation technique is left

atrial–esophageal fistula. This complication wasfirst recognized by surgeons performing RF

ablation intraoperatively and is manifested gen-

erally by stroke occurring several days to weeks

after the procedure because of air embolus.67,68

Sepsis syndrome and hematemesis may also

occur. Case fatality rate appears to be high, with

2 deaths reported so far in the EP literature.69,70

Recognition of this potential complication hasled to modification of the procedure, which may

include preprocedure identification of the esoph-

agus by MRI or CT, monitoring of esophageal

location with barium suspension or nasogastric

tube during ablation, and reduction of temper-

ature and power settings for ablation in the

posterior LA and/or eliminating these lesions

altogether (Fig 6).71

Pericardial tamponade is a complication com-

mon to all invasive cardiac procedures but

appears to be higher in AF ablation, likely due

to prolonged procedure duration, transseptal

access, multiple ablation lesions, and need

for prolonged high-dose heparinization during

the procedure. Although the rate of pericardial

tamponade was 107 (1.22%) of 8745 procedures

Fig 6. Fluoroscopic image of the LA in right anterioroblique view, similar to Fig 3. The ESO is outlined withbarium paste. Two TS are deployed, along with a CScatheter. Note the close relationship of the esopha-gus to the posterior left atrial wall. Abbreviations: ESOindicates esophagus; TS, transseptal sheaths; CS,coronary sinus.

in the Worldwide Registry, there were no report-

ed fatalities.62

Concern about prolonged fluoroscopy expo-sure during AF ablation procedures has also

been raised, but radiation dose appears to be

decreasing with increasing procedural experi-

ence and modification of the technique. Recent

data from our institution directly measuring

radiation dose in 15 patients undergoing AF

ablation and comparison with 15 controls un-

dergoing supraventricular tachycardia ablationshow that, with proper fluoroscopy settings,

patient radiation exposure can be kept within

safe and acceptable limits.72

Balanced against these known risks is the

evidence that catheter ablation for AF is effica-

cious in reducing or eliminating symptoms of

AF, which are frequently disabling, and that

rhythm control in selected patients can improvequality of life (QOL). Patients with AF may

have symptoms caused by a variety of causes,

including palpitations from rapid or irregular

ventricular response, diminished cardiac output

because of loss of atrial contribution to ventric-

ular filling, and failure of cardiac output to

meet metabolic demand during exertion. Dorian

et al demonstrated that patients with paroxys-mal or persistent AF have QOL which is as

poor as patients with chronic congestive heart

failure (CHF).73 Limitations to antiarrhythmic

drug therapy for AF have been well docu-

mented by recent large clinical trials.74,75

However, Purerfellner et al76 demonstrated that

QOL, as measured by SF-36, improved mark-

edly in 89 patients 6 months after undergoingPV isolation for paroxysmal AF to a level equiv-

alent to healthy matched controls. As expected,

improvement was greatest in patients with com-

plete (55%) or partial (34%) clinical response

to ablation.

Hsu et al77 studied 58 patients with AF and

CHF, most with decreased LV ejection fraction,

who underwent a combination of PV isolationand left atrial linear lesions and compared results

to 58 matched patients without CHF and with

normal LV function. They achieved sinus rhythm

without antiarrhythmic drugs in 70% of patients

in each group. CHF patients demonstrated

dramatic improvements in LV function, with

mean LVEF improvement from 0.35 to 0.55 and

corresponding decreases in LV end-diastolic

MARINE, DONG, AND CALKINS188

diameter, indicating reverse remodeling. CHF

patients and non-CHF patients both demonstrat-

ed significant and equivalent improvements inexercise capacity and QOL scores. Results were

seen at 3 months and were sustained through

12 months of follow-up.

Pappone et al78 recently reported intriguing

preliminary results suggesting that AF ablation

may improve mortality in selected patients. They

examined results of 1171 consecutive patients

with AF referred to their center for treatmentover a 38-month period who were followed up

for a mean of 900 days. Although not random-

ized, half the patients were treated with CPVA,

and half were treated medically. Approximately

20% of patients in each group completed serial

QOL assessments. Patients were remarkably well

matched for baseline characteristics. Patients

treated with catheter ablation were approximate-ly half as likely to die during the follow-up

period (6.5% vs 14%) and half as likely to have a

stroke or other major adverse cardiovascular

event (7.8% vs 16.8%) as those treated medical-

ly. Patients treated with ablation, but not those

treated medically, enjoyed improvement in

QOL scores to near normal levels. These results

stand in marked contrast to the results of ran-domized trials comparing medical rate-control

and rhythm-control strategies for treatment of

AF, in which no superiority for rhythm control

was demonstrated.74,75 Although the results of

Pappone et al78 need to be confirmed in a

multicenter randomized trial, they suggest that

adverse events and poor results associated with a

medical rhythm-control strategy may be associ-ated with antiarrhythmic drugs rather than the

strategy itself.

Current Approach to CatheterAblation of AF

At Johns Hopkins Hospital, we offer catheter

ablation of AF to patients with paroxysmal,

persistent, or permanent AF who have failed atleast 1 antiarrhythmic agent and are highly

symptomatic. We have no specific age, left atrial

size, or LV ejection fraction cutoff for the

procedure. Based on our experience, and also

the experience of others, we now use a modified

approach to catheter ablation of AF which we

call the bPappone PlusQ procedure. With this

technique, our goal is to create 2 wide encircling

lesions around the left and right PVs (bPapponeQ)and also to create entrance block into the PVs(bPlusQ). In contrast to the standard Pappone

circumferential ablation procedure, we do not

routinely create linear lesions between the circles

nor to the mitral valve annulus, thus minimizing

the risk of proarrhythmia caused by left atrial

flutters. We also routinely place a circular

mapping catheter in the PVs and deliver addi-

tional RF pulses along the encircling lesions untilcomplete electrical isolation of each PV is

achieved. With this technique, our single proce-

dure efficacy varies from 60% to 80%, depending

on the type of AF and patients’ clinical character-

istics. With a second procedure, the success rate

varies from 70% to 90%. In the most recent series

of 150 patients, there have been no strokes,

1 pericardial tamponade, and no severe stenosesof a major PV.

Future Approaches to CatheterAblation of AF

Fueled by encouraging results and potentially

broad applicability, further development of AF

catheter ablation technology can be anticipated

as part of a continued effort to improve proce-dural success and long-term outcomes and to

reduce complications rates. Cryoablation has

emerged as a promising new therapy which

may have applicability for catheter ablation of

AF.64,65 Advantages of cryoablation include

elimination of coagulum formation, which

should reduce stroke risk, and absence of

coagulative necrosis of ablated tissue, whichmay reduce risk of tamponade, PV stenosis, and

pericarditis.79 There remain some concerns with

ability of catheter cryotherapy to create durable

long-term lesions, and so studies of efficacy will

need to be performed.

Techniques to deliver simplified circumferen-

tial ablation lesions using balloon-tipped cath-

eters have been in development as well.Preliminary results of 1 ultrasound balloon

catheter for PV isolation have not been followed

by larger studies of efficacy and safety.80 Our

institution has been involved in the develop-

ment of a new technology using focused

ultrasound to improve energy delivery outside

the targeted PV ostium.81 Preliminary work in

CATHETER ABLATION THERAPY FOR ATRIAL FIBRILLATION 189

animal experiments has been encouraging, and

a phase I clinical trial is in progress.

Because of the technical complexity of catheterablation for AF, improvement in mapping tech-

nology promises to yield important benefits.

Three-dimensional mapping systems used to

guide CPVA will soon be able to import CT and

MRI images of the LA and PVs to enhance

mapping accuracy and provide greater detail of

the PV ostium–LA junction.82 Use of a magnetic

guidance system (Niobe, Stereotaxis; St. Louis,MO) to enable remote manipulation of the

ablation catheter has been reported in several

patient series and may allow for simpler and safer

placement of complex RF lesion sets.83,84 Finally,

work in our institution in a swine model has

shown feasibility of using stereotactic MRI guid-

ance to deliver RF lesions.85 This modality shows

potential to reduce fluoroscopy exposure andperhaps to improve precision of lesion delivery

around the PVs.

Summary and Conclusions

In the 11 years since catheter ablation of AF was

first reported, the procedure has undergone

rapid evolution with corresponding improve-

ment in procedural success and reduction in

complications. More needs to be learned about

the mechanism of AF in various patient pop-

ulations and about how to apply this information

to tailor the ablation procedure to individualpatients. More uniform reporting of results and

longer term follow-up are needed to confirm

durability of the short- and medium-term results

reported to date. Because of the technical

complexity of the procedure and lower success

rates and higher complication rates when com-

pared with ablation of SVT, catheter ablation of

AF is probably still best performed in experi-enced EP centers dedicated to carefully examin-

ing and reporting their results. With further

improvements in this growing and important

field, catheter ablation of AF may soon become

more broadly applied.

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