Selective Atrial Vagal Denervation Guided by Evoked Vagal Reflex to Treat Patients With Paroxysmal...

Darrieux, Ivani Trombetta, Carlos Eduardo Negrão and Eduardo SosaMauricio Scanavacca, Cristiano F. Pisani, Denise Hachul, Sissy Lara, Carina Hardy, Francisco

Paroxysmal Atrial FibrillationSelective Atrial Vagal Denervation Guided by Evoked Vagal Reflex to Treat Patients With

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Selective Atrial Vagal Denervation Guided by Evoked VagalReflex to Treat Patients With Paroxysmal Atrial Fibrillation

Mauricio Scanavacca, MD, PhD; Cristiano F. Pisani, MD; Denise Hachul, MD, PhD;Sissy Lara, MD, PhD; Carina Hardy, MD; Francisco Darrieux, MD, PhD; Ivani Trombetta, PhD;

Carlos Eduardo Negrão, PhD; Eduardo Sosa, MD, PhD

Background—The aim of this study was to evaluate whether selective radiofrequency (RF) catheter ablation of the atrialsites in which high-frequency stimulation induces vagal reflexes prevents paroxysmal atrial fibrillation (AF).

Methods and Results—Ten patients with episodes suggestive of vagal-induced paroxysmal AF and no heart disease wereselected for percutaneous epicardial and endocardial mapping of the atria to search for sites in which high-frequencytranscatheter stimulation (20 Hz,) induced vagal reflexes. A vagal response defined as AV block of �2 seconds waselicited in 7 of 10 patients (70%) with an average of 5�2.4 (range, 2 to 9) sites per patient, and RF pulses (21.0�12.0per patient) were applied at those sites to eliminate all evoked vagal reflexes. The 3 patients in whom evoked vagalreflexes were not obtained underwent circumferential pulmonary vein ablation with an average of 58.0�13.9 RF pulsesper patient (P�0.022). Autonomic evaluation was performed before and 48 hours and 3 months after the procedure andwas consistent with vagal withdrawal in all patients. Two of the 7 patients who underwent denervation remainedasymptomatic without the use of antiarrhythmic medication at a mean follow-up of 8.3�2.8 months (range, 5 to 15months); 4 had frequent recurrences and were referred for circumferential pulmonary vein ablation; and 1 had few AFepisodes without antiarrhythmic medication. The 3 patients without evoked vagal reflexes who underwent circumfer-ential pulmonary vein ablation remained asymptomatic without antiarrhythmic medication. One patient had acutedelayed gastric emptying after atrial vagal denervation.

Conclusions—RF catheter ablation of selected atrial sites in which high-frequency stimulation induced vagal reflexes mayprevent AF recurrences in selected patients with apparently vagal-induced paroxysmal AF. (Circulation. 2006;114:876-885.)

Key Words: catheter ablation � fibrillation � nervous system, autonomic

Atrial fibrillation (AF), the most common sustained car-diac arrhythmia, frequently is refractory to antiarrhyth-

mic (AA) drugs.1,2 Pulmonary vein (PV) radiofrequency (RF)catheter ablation procedures have been performed as analternative treatment for such patients. The effectiveness ofcatheter ablation is related to the extension of atrial lesionscreated around the PV ostia that aims empirically to eliminatethe triggers and change the substrate for AF maintenance.3–7

However, these lesions create large areas of scarring in theatria that might be substrates for atrial tachycardias anddepress left atrial contractility.8,9

Clinical Perspective p 885Vagal tone is a trigger for AF events in a subset of patients.10

In canine models, vagal stimulation shortens the effective atrialrefractory period and triggers and maintains AF.11–13 Further-more, selective vagal denervation prevents vagal-induced AF.14

In humans, some data suggest that adjunctive vagal denervationduring PV ablation significantly reduces AF recurrences.7,15

We hypothesized that selective atrial vagal denervationalone could prevent vagal-induced paroxysmal AF.

Methods

PatientsWe prospectively selected 10 patients with paroxysmal AF to receiveselective vagal atrial denervation between November 2004 and June2005. Inclusion criteria were documented episodes of symptomaticparoxysmal AF refractory to at least 2 AA drugs, age between 18 and65 years, no heart disease, and onset of AF episodes suggesting vagaltone predominance such as documented episodes during sleep andrest, after meals, or after vasovagal syncope. Exclusion criteria wereprevious AF catheter ablation, persistent AF for �48 hours, sinusnode and AV conduction disturbances, a permanent pacemaker, anddiagnosis of any structural heart disease after clinical evaluation,ECG, echocardiography, Holter monitoring, and treadmill stresstesting. Patients with thyroid dysfunction, diabetes mellitus, lungdiseases, and renal and hepatic failure also were excluded. Allpatients provided written informed consent to take part in this study.

Received April 19, 2006; revision received June 30, 2006; accepted July 6, 2006.From the Heart Institute, University of São Paulo Medical School, São Paulo, Brazil.Correspondence to Dr Mauricio Scanavacca, Unidade Clínica de Arritmia, Heart Institute of the University of São Paulo Medical School, Av Dr Eneas

Carvalho de Aguiar 44, CEP 05403-000, São Paulo/SP, Brazil. E-mail [email protected]© 2006 American Heart Association, Inc.

Circulation is available at http://www.circulationaha.org DOI: 10.1161/CIRCULATIONAHA.106.633560

876

Arrhythmia/Electrophysiology

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Autonomic EvaluationAA drugs were discontinued for at least 5 half-lives; amiodarone wasdiscontinued for 1 month. Heart rate variability (HRV) was used asan indicator of autonomic activity. Heart rate (HR) and time-domainand frequency-domain HRV were analyzed from 24-hour Holtermonitoring and tilt-table testing before and 48 hours and 3 monthsafter ablation. All 24-hour Holter ECG recordings were obtained inaccordance with standard guidelines.16 After automatic analysis, thedata file was visually reviewed and edited by one of the investiga-tors. HRV was performed with Marquette Holter Analysis Software(Marquette Medical Systems, Milwaukee, Wis). Premature ventric-ular beats, electrical noise, or other aberrant ECG signals wereexcluded from HRV analysis. Time-domain measures were the SDof all normal R-R intervals in the 24-hour ECG recording (SDNN),the square root of the mean squared differences of successive NNintervals (rMSSD), and the percentage of sinus cycles differing fromthe preceding cycle by �50 ms over the entire 24-hour recording(pNN50). Power spectral analysis (computed by fast Fourier trans-formation) of all normal R-R intervals also was performed.

Time-domain measures and power spectral analysis (computed byfast Fourier transformation) also were analyzed during tilt-tabletesting with specific software (WinCPRS version 1.155, AbsoluteAliens Ay, Turku, Finland) in 5-minute segments, ie, after the patientrested for 30 minutes in the supine position and after the first 5minutes after orthostatic exposure. Three frequency-domain mea-sures of HRV were obtained: very low-frequency (LF) power (0.00to 0.04 Hz), LF power (0.04 to 0.15 Hz), and high-frequency (HF)power (0.15 to 0.40 Hz). The power of each frequency band waslogarithmically transformed to avoid the undue influence of extremevalues; this was expressed in milliseconds squared. The sympathetic-vagal balance evaluation was based on frequency-domain HRVanalysis (LF/HF relation).

Electrophysiological StudyPatients underwent electrophysiological study while in a fasting stateand anesthetized. Three multipolar catheters were placed into thecoronary sinus, around the tricuspid annulus, and on His bundleposition, respectively. Intracardiac electrograms were filtered atband-pass settings from 80 to 500 Hz and displayed simultaneouslywith ECG leads I, II, III, V1, and V6 on a multichannel recorder (EPTracer, CardioTek, Maastricht, the Netherlands). A programmeddigital stimulator (EP Tracer) was used to deliver electrical impulsesof 2-ms duration at twice the diastolic threshold. Programmed atrialstimulation was performed in the high right atrium and coronarysinus with up to 2 extrastimuli during 2 different pacing cycle lengths(600 and 400 ms), followed by continuously and decrementallyreducing the pacing cycle length up to 200 ms to access supraven-tricular tachycardia, atrial flutter, and AF induction. Intravenousadenosine (18 mg) and isoproterenol (up to 30 �g) also were infusedin bolus to evaluate AF induction.

Identification and RF Ablation of AutonomicAtrial InnervationThe left atrium was accessed from the epicardial and endocardialsurfaces. One quadripolar catheter with a 4-mm or 8-mm tip(Biosense, Diamond Bar, Calif) was introduced into the pericardialspace by the subxyphoid approach as previously described.17 An-other 4-mm-tip catheter (Biosense) was introduced into the leftatrium through a long sheath by the transseptal approach. Heparinwas infused (10 000-IU bolus) through the sheaths, and the activatedclotting time was evaluated every 30 minutes to maintain theactivated clotting time between 250 and 300 seconds.

Atrial ablation target sites were identified as the places wherevagal reflexes evoked by transcatheter HF stimulation were obtained.Rectangular electrical stimuli were delivered at a frequency of 20Hz, amplitude up to 100V, and pulse duration of 4 ms (GrassStimulator S-48, Astro Med Inc, Grass Instruments Division, WestWarwick, RI).

Vagal reflex was defined as AV block �2.0 seconds that occurredafter HF stimulation (Figure 1). If a reflex was elicited, RF energy

was delivered (60°C, 30 to 50 W for 60 seconds, Stokert, Biosense)at the epicardial or endocardial sites where HF stimulation inducedevoked vagal reflexes. The end point of ablation was defined as thefailure to reproduce vagal reflexes with repeated HF stimulation.Complete vagal denervation was defined arbitrarily as the abolitionof all vagal reflexes evoked by HF stimulation.

Pulmonary Vein IsolationPV isolation was performed in patients in whom a vagal reflex wasnot induced or in cases of late AF recurrences during follow-up aftersuccessful vagal denervation. A circular decapolar (Lasso, Biosense)catheter was introduced in the left atrium by a long sheath throughthe transseptal approach. One 7F 8-mm-distal-tip electrode (Bio-sense) also was introduced into the left atrium by a second transsep-tal puncture. Heparin was infused (10 000-IU bolus) through thesheaths, and the activated clotting time was evaluated every 30minutes to maintain the activated clotting time between 250 and 300seconds. PV angiographies were performed by using one of the longtransseptal sheaths, except for the right inferior PV, which was notsystematically evaluated.

The Lasso catheter was placed on the PV ostia, and RF pulses (20to 50 W, 55°C, 15 to 60 seconds) were applied to encircle the PVs1 to 2 cm from their ostia. The end point was a reduction of at least80% of atrial electrogram amplitude and PV disconnection. RFapplications on the left posterior wall were monitored by anesophageal thermometer (Precision 4000A Thermometer, YSI Tem-

Figure 1. Vagal response (pause, 2.28 seconds) elicited duringepicardial HF stimulation (20 Hz). Note the close relationshipbetween the esophageal probe and the epicardial catheter(4-mm tip). To avoid esophageal damage, RF was deliveredfrom the endocardial catheter (8-mm tip), limiting energy to 30W and 55°C, and the epicardial catheter was positionedbetween the endocardial catheter and esophagus probe. Thehighest esophageal temperature recorded was 37.5°C, and thevagal reflex evoked by epicardial stimulation was completelyabolished. CS indicates coronary sinus; LA catheter, left atrialendocardial catheter; and RV catheter, right ventricle endocar-dial catheter.

Scanavacca et al Vagal Denervation and Paroxysmal Atrial Fibrillation 877



perature, Dayton, Ohio), and energy delivery was limited by esoph-ageal temperature elevation up to 37.5°C. Adenosine (12 to 18 mgIV) and isoproterenol (10 to 30 �g IV) were infused in bolus toidentify PV reconnection or ectopic triggers outside the veins.

Postablation Follow-UpAfter ablation, patients received subcutaneous enoxaparin (0.5mg/kg twice a day) started 6 hours after the end of the procedure andmaintained until adequate levels of anticoagulation with oral warfa-rin were obtained (international normalized ratio, 2.0 to 3.0). Patientswere discharged without AA therapy and instructed to report anysymptoms. A Loop event record was recommended to document allpossible symptoms of AF recurrence. Holter monitoring also wasperformed 48 hours and 3 months after the procedure. Recurrence ofAF was defined as a sustained episode lasting �30 seconds. The endpoint of the study was considered freedom from late AF recurrencein patients with atrial vagal denervation.

Data AnalysisData are presented as mean�SD. The power of each frequency bandwas logarithmically transformed to normalize the distribution. Com-parisons within groups and different time sequences were done witha paired t test, whereas an unpaired 2-sample t test was used forcomparisons between groups. Differences were considered signifi-cant at values of P�0.05.

The authors had full access to the data and take full responsibilityfor their integrity. All authors have read and agree to the manuscriptas written.

ResultsPopulation CharacteristicsAll 10 patients had frequent episodes of symptomatic parox-ysmal AF documented by 12-lead ECG or 24-hour Holtermonitoring. All patients had no other associated diseases, andmost AF episodes were related to vagotonic tone (Figure 2).Clinical characteristics are shown in Table 1.

Electrophysiological StudyAnomalous pathways, AV reentrant tachycardia, and sus-tained atrial tachycardia were excluded by the electrophysi-ological test. Self-limited sustained AF was induced in 1

patient by intravenous adenosine and in another patient afterintravenous isoproterenol. Programmed atrial stimulation in-duced sustained AF in 2 patients and atrial flutter in 2 others.

Localization of Vagal Innervation Atrial SitesAtrial HF stimulation induced sustained AF in all patients. Avagal response was elicited in 7 of 10 patients (70%) with anaverage of 5�2.4 sites per patient. HF stimulation at thesesites caused immediate vagal reflexes (Figure 3). We beganeliciting vagal reflexes from the epicardium and attempted toeliminate the response by RF application at the same place.However, when that place was too close to the esophagus,phrenic nerves, aorta, or coronary arteries, we changed thesite of ablation to the endocardium. The most commonepicardial sites were the left atrial (LA) posterior wall(catheter inside the oblique sinus) and close to the rightinferior PV in 7 patients (100%), right superior PV in 5patients (71%), left inferior PV in 5 patients (71%), and leftsuperior PV in 3 patients (42%). In 4 patients, vagal reflexeswere elicited in the posterior region between the inferior PVand coronary sinus ostium and along the esophagus position.In 3 patients, vagal reflexes also were elicited on the anteriorand superior LA wall with the catheter positioned inside thetransverse sinus and less frequently on the lateral sites of PVsexplored outside the oblique sinus (Figure 3A).

The most common endocardial sites where vagal responsewas elicited were between the right inferior PV and LA in 4patients (57%), between the LA and right superior PV in 2patients (28%), and between left inferior and superior PV in2 patients (28%) (Figure 3B). In 2 patients, reflex sites werethe interatrial septum, the LA roof, and the coronary sinusostium.

We were not able to elicit a vagal reflex stimulatingepicardial or endocardial sites in 3 patients (patients 2through 4). However, HF stimulation induced sustained AFand elicited right and left phrenic stimulation in all thesepatients.

Figure 2. Example of AF during tilt-tabletesting. Ten minutes after exposure inthe upright position, the patient devel-oped a mixed vasovagal reflex and expe-rienced syncope. The ECG recorded dur-ing the procedure showed the onset ofAF immediately after the vasovagalreflex.

878 Circulation August 29, 2006



RF Ablation

Vagal Atrial DenervationOne to eight (average, 4.3�1.6) RF applications were re-quired to eliminate the evoked vagal reflex at the same site,and an average of 21�12 RF pulses per patient were neededto completely eliminate the response at all sites in the 7patients with induced reflexes (10.1�8.2 pulses at epicardialsites and 10.9�8.2 pulses at endocardial sites; P�NS). In 1patient (patient 1), RF pulses were applied just to theepicardial surface; in 2 patients (patients 6 and 10), just to theendocardium; and in 4 patients, to both. When evoked vagalreflex sites were too close to the esophagus, we delivered RFfrom the endocardium, positioning the epicardial catheterbetween the endocardial catheter and esophagus to avoid anincrease in esophageal temperature. Evoked vagal reflexeswere not observed during RF applications, except in 1 patient.In general, either no change occurred or an increase occurredin mean HR during RF application. The mean procedure timewas 265.7�56.2 minutes, and mean x-ray time was 74.7�7.5minutes. No complications were observed at the end of theprocedures.

Pulmonary Vein IsolationA mean of 58.0�13.9 RF pulses were applied to completelyisolate the 4 independent PVs in patients 2 and 3 and the lefttrunk and 2 right PVs in patient 4. The mean procedure timeand mean x-ray time were 240�87.2 and 78.7�5.5 minutes,respectively. Evoked vagal reflex was not observed in anypatient during RF applications. No complications were ob-served at the end of the procedures. Significantly fewer RFpulses were applied to abolish vagal response than to isolatethe PV (21.0�12.0 versus 58.0�13.9; P�0.022).

Clinical OutcomePatients had a mean follow-up of 8.3�2.8 months (range, 5 to15 months). Of the 7 patients in whom vagal denervation wasobtained (average follow-up, 7.7�3.2 months; range, 5 to 15months), 5 (71.4%) had AF recurrence: 4 in the first weekafter the procedure and 1 after 4 months of follow-up (Figure4). All 4 patients who had early recurrence of AF also had late

Figure 3. Atrial epicardial (A) and endocardial (B) sites where HFstimulation evoked a vagal response. Epicardial (C) and endo-cardial (D) sites where RF ablation abolished the evoked vagalresponse (absolute number of sites).

TABLE 1. Baseline Characteristics of the Patients (n�10)

Age (range), y 45.2�10.1 (30–61)

Male sex, n (%) 9 (90)

Paroxysmal AF, n (%) 10 (100)

Vagal-induced AF, n (%) 10 (100)

Sleep, n (%) 6 (60)

After meal, n (%) 3 (30)

After vasovagal reflex, n (%) 4 (40)

Table-tilt test response, n (%)

Negative 6 (60)

Positive mixed 4 (40)*

Echocardiogram

Left atrium, mm 36.8�6.7 (27–45)

LV end-diastolic diameter, mm 47.8�4.2 (40–53)

LV end-systolic diameter, mm 30.2�4.1 (24–36)

LV ejection fraction, (%) 67.0�4.7 (60–77)

Holter

Heart rate

Minimum 42.4�6.5

Average 64.3�5.5

Maximum 111.6�20.0

Time-domain HRV

SDNN 164.6�8.2

pNN50 29.4�19.1

rMSSD 55.2�24.0

Frequency-domain HRV

LF, ms2 12 111�921

HF, ms2 552.5�564.8

LF/HF 1.6�0.3

Atrial ectopy, n/h 8.2�8

Ventricular ectopy, n/h 0.8�2.0

LV indicates left ventricular.*AF induced after positive tilt-table test in 1 patient.

Figure 4. Kaplan-Meier curve indicating freedom from recur-rence of AF in patients who underwent selective atrial vagaldenervation guided by evoked vagal response (continuous blueline) and after PV isolation (dotted red line) (n�10).




recurrences despite the AA drugs and were referred for PVisolation after 3 months. One patient continued under clinicalobservation without AA therapy for sparse, short episodes ofAF. Two patients remained asymptomatic without AA andwithout AF episodes on Loop and Holter monitoring record-ings. The 3 patients who underwent PV isolation remainedfree of recurrence without AA drugs. Inappropriate sinustachycardia (HR �100 bpm at rest) was not observed in anypatient. Patient 8 had acute delayed gastric emptying afteratrial vagal denervation. Clinical manifestations began on theday after the procedure and persisted for 1 week. Stomach-emptying scintillography performed on the sixth day showedsignificant stomach emptying delays (78% retention after 4hours) that returned to normal at the 3-month evaluation.

Effects of Atrial Vagal DenervationMinimal and mean HRs significantly increased after vagaldenervation. Table 2 and Figure 5 show changes in sinusrhythm rate after acute and chronic vagal denervation. Aftercircumferential PV ablation (CPVA), minimal and mean HRsalso changed significantly, indicating that extensive ablationof PV antrum also changes the autonomic tone. Minimum HRearly after the procedure was higher after CPVA than aftervagal ablation (P�0.05). Time-domain HRV parameterssignificantly decreased after vagal denervation; this differ-ence also was observed after CPVA (Tables 2 and 3, Figures5 and 6). After 3 months, time-domain and frequency-domainanalysis remained different from baseline. Although the HFspectrum decreased on frequency-domain HRV analysis afterthe procedure, no difference was observed on sympatheticvagal balance analysis (LF/HF, 1.61, 2.02, and 1.89 before,soon after, and late after the procedure, respectively; P�0.18)because of a proportional decrease in LF spectrum compo-

nents. These data suggest that sympathetic fibers also weredestroyed after vagal denervation and CPVA.

Clinical and Autonomic Patterns of AtrialDenervation and AF RecurrenceThe autonomic characteristics of patients are shown in Tables2 and 3. In the whole population, HR and HRV parameterschanged significantly for all variables except maximal HR.Time-domain HRV parameters and frequency-domain pa-rameters decreased after the procedure, and all differencespersisted after 3 months. Patients who underwent PV antrumisolation and those who underwent vagal denervation thatremained without AF recurrence had a significant increase inminimum HR (P�0.05) and a trend in decreasing naturallogarithm of low-frequency (LnLF) power spectra (P�0.09)compared with patients with recurrences during thefollow-up.

DiscussionThe main findings of this study are that vagal reflexes can beinduced by transcatheter HF stimulation of select epicardialand endocardial areas of the LA in most patients withparoxysmal AF. RF catheter ablation of these areas eliminatessuch responses and promotes autonomic changes, suggestingvagal tonus withdrawal. However, these parasympatheticchanges obtained without PV disconnection were enough toprevent clinical AF episodes in few selected patients. Addi-tionally, this study suggests that extensive PV antrum abla-tion itself promotes left atrial autonomic denervation even inpatients in whom evoked vagal reflexes could not be elicitedby HF atrial stimulation.

TABLE 2. Holter Monitoring Data of All Patients Before, Soon After, and LateAfter AF RF Catheter Ablation Guided by Evoked Vagal Reflex or PV Isolation

Soon After Late After

Before Mean�SD Mean�SD P * Mean�SD P *

Heart rate, bpm

Minimum 42.4�6.5 62.0�15.6 0.005 56.0�7.3 0.0008

Average 64.3�5.4 82.0�14.5 0.006 76.3�4.6 0.0001

Maximum 111.6�20.0 124.8�25.3 0.251 131.1�18.0 0.054

Time-domain HRV

SDNN 164.6�8.2 71.8�45.3 0.0002 91.4�25.1 �0.0001

pNN50 29.4�19.1 2.1�3.0 0.032 1.5�1.6 0.030

rMSSD 55.2�24.0 15.6�8.2 0.018 19.0�6.8 0.026

Frequency-domain HRV

LnLF, ms2 6.85�0.82 3.97�1.85 0.003 5.33�1.33 0.035

LnHF, ms2 5.99�0.86 3.0�1.19 0.0003 4.1�0.75 0.004

LF/HF 1.6�0.3 1.9�0.7 0.29 2.0�0.7 0.18

Atrial ectopy, n/h 27.1�53.8 6.0�6.1 0.34 9.6�11.5 0.42

Ventricular ectopy, n/h 0.8�2.0 39.6�83.7 0.267 3.4�4.9 0.240

LnLF indicates natural logarithm of low-frequency power; LnHF, natural logarithm of high-frequency power.

*Compared with before ablation.




Selective Vagal Denervation Strategy forParoxysmal AF AblationClinical features and ECG monitoring of paroxysmal AFonset have strongly suggested that vagal activity increases

before the initiation of the AF episodes in a select group ofpatients.10,18 Animal model studies have demonstrated thatvagal activity increases vulnerability for AF by shortening theatrial effective refractory periods and increasing spatial atrial

Figure 5. Changes in HR and HRV on Holter monitoring before, soon after, and late after selective atrial vagal denervation guided byevoked vagal response (blue continuous line) and after CPVA (red dashed line). Data for probability values were obtained during differ-ent time sequences. *P�0.05, #P�0.10.




heterogeneity.11–13 A recent animal study also suggests thatselective vagal denervation decreases the probability of in-ducing and maintaining AF.14 Therefore, vagal activity atten-uation by selective ablation of vagal atrial innervation mightbe a logical strategy to treat select patients with vagal-induced AF.

Vagal Denervation Guided by Elicited Vagal ReflexTransient sinus bradycardia, sinus arrest, and hypotensionhave been reported during RF-catheter PV ostial abla-tion.7,19,20 Such reflexes were initially reported as a compli-cation of focal ablation, and thermal stimulation of afferentvagus nerve fibers was considered the cause. Its incidencewas 15% when low-power and more localized RF ablationwas performed inside the PV ostia but increased to 34% whenhigh-power and extensive endocardial RF ablation was per-formed around the PV antrum.7,19,20 In our study, just 1patient had vagal reflexes during RF delivery in areasselected by HF stimulation. The incidence was closer to thatof Hsieh et al20 and Lemery et al,21 probably because wedelivered lower RF power and the ablated area was morerestricted. However, it was an unexpected find. Our initialexpectation was that a very high incidence of vagal reflexeswould be elicited during RF delivery at sites selected withvagal innervation identified by HF stimulation. In fact, duringRF delivery, HR increased instead. This could be interpretedas an immediate withdrawal of vagal activity resulting fromrapid inhibition of the atrial autonomic ganglia plexuses

activity responsible for the autonomic control of the heart.This response was independent of endocardial or epicardialdelivery of RF energy.

Atrial Vagal Denervation Guided by HF StimulationSchauerte et al14 demonstrated in dogs that the major para-sympathetic pathways to the atria can be identified bytransvenous HF stimulation. RF catheter ablation of theseparasympathetic nerves prevented the induction and mainte-nance of AF during vagal stimulation. A preliminary reportby Nakagawa et al15 suggests that patients randomized to PVisolation plus atrial denervation guided by HF stimulationexperience a significant reduction in AF recurrence duringfollow-up compared with patients randomized to lone PVisolation. That observation is in accordance with observationsof Pappone et al,7 who suggested that adjunctive vagaldenervation during CPVA significantly reduces the recur-rence of AF. The present study is the first attempt to promoteselective vagal atrial denervation as a lone strategy to treatpatients with paroxysmal AF. Our results confirm that thisapproach is feasible, but its effectiveness is low when appliedas the only procedure in patients with paroxysmal AF.Because we selected patients with a clear vagal-induced AF,it is reasonable to suppose that vagal denervation guided byHF stimulation did not produce the necessary autonomicmodification to prevent AF in our patients. In fact, patientswithout recurrences, including those in whom HF stimulationcould not elicit a vagal reflex and who underwent PV antrum

TABLE 3. Table-Tilt Test Analysis of All Patients Before, Soon After, and LateAfter AF RF Catheter Ablation Guided by Evoked Vagal Reflex or PV Isolation

Soon After Late After

Before Mean�SD Mean�SD P * Mean�SD P *

Rest

Heart rate (average), bpm 60.8�6.7 78.3�14.6 0.012 72.5�9.7 0.008

Time-domain HRV†

SDNN 41.5�15.7 18.4�12.5 0.006 27.9�13.4 0.078

rMSSD 25.6�11.4 11.3�9.3 0.016 14.9�8.4 0.048

Frequency-domain HRV‡

LnLF 5.83�1.15 2.69�2.08 0.003 4.62�1.49 NS

LnHF 4.65�1.02 2.46�1.60 0.007 3.84�1.03 NS

LF/HF 3.95�2.53 2.70�3.03 NS 3.88�4.33 NS

Upright (5 min)

Heart rate (average)† 87.7�14.9 96.4�17.9 NS 90.0�13.1 NS

Time-domain HRV

SDNN 52.9�26.6 30.5�22.3 0.091 35.7�20.2 NS

rMSSD 25.4�19.4 7.3�3.5 0.034 12.3�7.1 NS

Frequency-domain HRV‡

LnLF 5.85�1.49 3.17�2.25 0.016 4.82�1.90 NS

LnHF 4.17�0.85 1.87�1.10 �0.001 3.14�1.09 0.038

LF/HF 8.84�8.15 8.39�13.73 NS 10.42�9.97 NS

LnLF indicates natural logarithm of low-frequency power; LnHF, natural logarithm of high-frequency power.

*Compared with before ablation.†All-period analysis of time-domain HRV.‡Five-minute frequency-domain HRV analysis.




ablation, had more significant changes in HRV parameterscompared with patients with AF recurrences. This observa-tion suggests that some atrial sites with vagal innervationwere not identified during HF stimulation once extensiveempirical ablation of the PV antrum promoted a moresignificant autonomic change. Otherwise, a nonhomogeneousatrial denervation might also propitiate a favorable conditionfacilitating sustained AF. Olgin et al22 demonstrated thatsympathetic stimulation blunts the decrease in effectiverefractory period induced with vagal stimulation in normalatrial myocardium. When innervation is made heterogeneousby regional sympathetic denervation, dispersion of refracto-riness is increased, and AF can be sustained without vagalstimulation. In the present study, we attempted to selectivelyablate the vagal fibers on the basis of vagal reflex induced byHF stimulation. However, recent anatomic studies havedemonstrated that in human hearts the autonomic nervoussystem is organized in a complex network connecting fibersfrom the central nervous system with the ganglionated atrialplexuses that also are connected to the conduction system ofthe heart (sinus node and AV node). The atrial autonomicganglia are distributed mainly around the PV antrum encom-passing sympathetic and parasympathetic fibers that share thesame ganglionated plexus.23 It seems that attempts to selec-tively ablate the vagal innervation on the atria cannot be

performed without a simultaneous ablation of some sympa-thetic fibers.

Localization of Vagal Innervation Atriaby HF StimulationWe designed this study on the basis of anatomic distributionof autonomic ganglionated plexus of the atria as described byArmour et al.23 Because preganglionic parasympathetic andpostganglionic sympathetic fibers come together in the fatpads on the epicardial surface of the LA posterior wall, weplanned to initiate the mapping and ablation of the autonomicganglia through the epicardial approach. Pericardial PVreflections form the oblique and transverse sinuses located atthe posterior and superior left atrial walls and facilitate astable catheter location on the epicardial atrial surface. Exceptin 3 patients in whom we could not elicit any vagal responseby HF stimulation, we localized most of our targets for RFablation in that area. Our findings are in accordance withthose described by Pappone et al7 and Lemery et al21 and arecomparable to the anatomic description of Armour et al,23

which shows autonomic ganglia distributions around theantrum of PV ostia in most patients. Although the epicardialapproach was useful for localizing the ganglia position, wefound some limitations to delivery of RF energy in someepicardial spots. In some locations, the absence of circulating

Figure 6. Changes in HRV on tilt-tabletest (rest and upright) before, soon after,and late after selective atrial vagal dener-vation guided by evoked vagal response(blue continuous line) and after CPVA(red dashed line). Data for probabilityvalues were obtained during differenttime sequences. *P�0.05, #P�0.10.




fluid and the closer contact to the tissue did not allow enoughRF power to be delivered. In other cases, RF application wasdone too close to the esophagus, phrenic nerves, aorta,coronary artery, and pulmonary artery, and we decided todeliver RF energy through the endocardial surface of the leftatrium. In such cases, new HF stimulation from the endocar-dium was performed, confirming the ganglia position. Usingthis strategy, we abolished all vagal reflexes elicited by theepicardial and endocardial HF stimulation.

Effects of Atrial Ablation on Autonomic ParametersPrevious studies have demonstrated that focal PV ablationand CPVA may result in a transient increase in HR and atransient decrease in time-domain and frequency-domainHRV, suggesting parasympathetic nervous withdrawal, en-hanced sympathetic activity, or a combination of both.7,19,20

Hsieh et al20 reported autonomic dysfunction with increasesin HR and decreases in the HRV parameters after ablation offocal AF originating from PVs. Independently of the presenceor absence of evoked-vagal response, all parameters recov-ered spontaneously after 1 month. Pappone et al7 reported thatpatients who had evoked vagal response during CPVA thatwas abolished by continuous RF delivery (vagal denervation)had a better outcome, and autonomic changes were moresignificant and remained for a longer time (3 to 6 months). Inthe present study, we observed autonomic changes similar tothose reported by these authors. HRV parameters and mini-mum and mean HRs increased significantly after the proce-dure and remained elevated at the 3-month evaluation.Time-domain measure analysis decreased and persisted untilthe 3-month evaluation. Patients who underwent PV isolationalso had similar behavior, but HR and HRV measurementshad a more significant acute change. When patients with AFrecurrences were compared, those free of recurrence hadmore significant decreases in HRV indexes that persistedafter the 3-month evaluation, as described previously.7

Safety of Vagal DenervationThree main concerns should be considered after vagal dener-vation: inappropriate sinus node tachycardia, fast AV nodeconduction during AF, and ventricular arrhythmias facilitatedby vagal tonus decrease in the ventricles. Hsieh et al20

reported 2 patients (6.7%) who had inappropriate transientsinus tachycardia after focal PV ablation. Pappone et al7 alsoreported 2 patients (8%) who developed inappropriate sinustachycardia after CPVA. All these patients had signals ofvagal denervation during the procedure that lasted up to 1month. In our study, despite the significantly increased meanHR after ablation, no patient had criteria for inappropriatesinus tachycardia. The mean HR during AF also increasedafter vagal denervation, which could be a possible cause forworsening of patient symptoms when the vagal denervationprocedure did not prevent AF recurrences. We did notspecifically evaluate the negative effects of vagal denervationon the ventricular electrophysiological parameters. Chiou andZipes24 reported that RF catheter ablation of 3 canine atrial fatpads abolished vagal modulated sinus arrhythmia, markedlydecreased HRV, and eliminated baroreflex sensitivity withoutaffecting vagal innervation of the ventricles or causing any

ventricular arrhythmias. Acute delayed gastric emptying last-ing 1 week was an unexpected complication observed in 1patient after vagal denervation. The left vagus branch runningon the esophageal anterior wall toward the stomach might bedamaged during left posterior wall ablation. This complica-tion was recently reported in 4 patients who underwent PVablation, with 1 patient needing a surgical procedure torestore gastric emptying.25

Study LimitationsThis study included a small number of patients. The high AFrecurrence rate observed during follow-up did not allow us tocontinue the protocol. However, this premature study inter-ruption did not disprove the hypothesis that AF induced byvagal activity could be treated by selective ablation ofautonomic ganglia. Patients who underwent RF ablationguided by vagal reflex induced by HF stimulation whoremained free of AF recurrence had an important autonomicchange at noninvasive evaluation. On the contrary, patientswithout success did not have the same level of autonomicchange. It also is possible that the methodology used tolocalize and eliminate such ganglia and vagal fibers was notcompletely effective. However, our observations suggest thatthe elimination of all evoked vagal reflexes induced by HFstimulation may prevent vagal-induced AF episodes in selectpatients. It seems that a critical change in cardiac autonomicbehavior at the end of the procedure is necessary whenselective autonomic denervation is proposed to treat patientswith paroxysmal AF.

ConclusionRF catheter ablation of select atrial sites in which HFstimulation induced vagal reflexes may prevent AF recur-rences in selected patients with apparent vagal-induced par-oxysmal AF.

AcknowledgmentWe thank Carlos Morillo, MD, for his suggestions during thepreparation of this manuscript.

Sources of FundingThe Heart Institute of the University of São Paulo Medical Schooland Zerbini’s Foundation supported the present study.

DisclosuresNone.

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CLINICAL PERSPECTIVEA better understanding of the electrophysiological mechanisms of cardiac arrhythmias has allowed many clinical disordersto be effectively treated in recent years. More recently still, electrophysiologists have focused on the treatment of atrialfibrillation (AF). However, regular procedures promote unspecific and extensive ablation of pulmonary vein ostia and leftatrial posterior wall. These lesions result in large areas of scarring in the atria, which might depress left atrial contractilityand create substrates for atrial tachycardia. Clinical features and animal model studies have strongly suggested that vagalactivity increases before the initiation of the AF episodes and that selective vagal denervation decreases the probability ofinducing and maintaining AF. Therefore, vagal activity attenuation by selective ablation of vagal atrial innervation mightbe a logical and specific strategy to treat patients with vagal-induced paroxysmal AF. This study assessed this hypothesisin 10 patients. Two of these patients had AF recurrences prevented after radiofrequency ablation of select atrial sites inwhich high-frequency stimulation induced vagal reflexes. The success obtained in these 2 patients creates a perspectivethat, with the improvement of techniques of atrial vagal denervation, AF might be abolished with more preservation of theatria. As in the past when the knowledge of cardiac arrhythmia mechanisms guided the development of specific techniquesto approach different mechanisms of supraventricular and ventricular tachycardias, a better understanding of AFmechanisms will guide the future development of effective and specific strategies that preserve the structure and functionof the heart.




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