ablation of ventricular arrhythmias in arrhythmogenic ... · pdf fileexecutive med director,...

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Ablation of Ventricular Arrhythmias in Arrhythmogenic Right Ventricular

Dysplasia/Cardiomyopathy: Arrhythmia-Free Survival after Endo-Epicardial Substrate

Based Mapping and Ablation

Running title: Bai et al.; Endo-epicardial ablation of VT in ARVD/C

Rong Bai, MD, FHRS1,8,*; Luigi Di Biase, MD, PhD, FHRS1,9,11,*; Kalyanam Shivkumar, MD2;

Prasant Mohanty, MBBS, MPH1; Roderick Tung, MD2; Pasquale Santangeli, MD1; Luis Carlos

Saenz, MD3; Miguel Vacca, MD3; Atul Verma, MD4, Yariv Khaykin, MD4; Sanghamitra

Mohanty, MD1; J. David Burkhardt, MD, FHRS1; Richard Hongo, MD5; Salwa Beheiry, RN5;

Antonio Dello Russo, MD7; Michela Casella, MD7; Gemma Pelargonio, MD6; Pietro Santarelli,

MD6, Javier Sanchez, MD1; Claudio Tondo, MD7; Andrea Natale, MD, FHRS1,10,11,12,13

1Texas Cardiac Arrhythmia Inst at St. David's Medical Ctr, Austin, TX; 2UCLA Cardiac Arrhythmia Center, Los Angeles, CA; 3Fundation Cardio Infantil, Bogota, Colombia; 4Southlake Regional Health Ctr,

Newmarket, Ontario; Canada; 5Division of Electrophysiology, California Pacific Medical Center, San Francisco, CA; 6Inst of Cardiology, Catholic Univ of the Sacred Heart, Rome, Italy; 7Centro Cardiologico Monzino, IRCCS, Milan, Italy; 8Dept of Internal Medicine, Tong-Ji Hospital, Tong-Ji Medical College, Huazhong Univ of Science & Technology, Wuhan, China; 9Dept of Cardiology, Univ of Foggia, Foggia,

Italy; 10Division of Cardiology, Stanford Univ, Palo Alto, CA; 11Dept of Biomedical Engineering, Univ of Texas, Austin, TX; 12School of Medicine, Case Western Reserve Univ, Cleveland, OH; 13Interventional

Electrophysiology, Scripps Clinic, San Diego, CA; *Drs. Bai and Di Biase are co-first authors.

Address for correspondence:

Andrea Natale, MD

Executive Med Director, TX Cardiac Arrhythmia Inst at St. David's Medical Ctr, Austin, TX,

Consulting Prof, Division of Cardio, Stanford Univ, Palo Alto, CA, Clinical Associate Prof of

Med, Case Western Reserve Univ, Cleveland, OH, Adjunct Prof, Dept of Biomedical

Engineering, Univ of Texas, Austin, TX, Director, Interventional Electrophysiology, Scripps

Clinic, San Diego, CA 3000 N. I-35, Suite 720; Austin, TX 78705

Tel: +15125448186; Fax: +15125448184

Email: [email protected]

Journal Subject Code: [22] Ablation/ICD/surgery

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rhythmia Inst at St. David's Medical Ctr, Austin, TX; UCLA CardC eo do e

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rhythmia Inst at St. David's Medical Ctr, Austin, TX; UCLA CardCA; 3Fundation Cardio Infantil, Bogota, Colombia; 4Southlake Reo; Canada; 5Division of Electrophysiology, California Pacific Medof Cardiology, Catholic Univ of the Sacred Heart, Rome, Italy; 7Ce

Milan, Italy; 8Dept of Internal Medicine, Tong-Ji Hospital, Tong-Ji cience & Technology, Wuhan, China; 9Dept of Cardiology, Univ oardiology, Stanford Univ, Palo Alto, CA; 11Dept of Biomedical En2S h l f M di i C W R U i Cl l d OH

by guest on October 19, 2017

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Abstract:

Background - In patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy

(ARVD/C), freedom from ventricular arrhythmias (VAs) after endocardial ablation is limited.

We compared the long term freedom from recurrent VAs by using endocardial-alone ablation vs.

endo-epicardial substrate based ablation.

Methods and Results - 49 patients with ARVD/C undergoing ablation of ventricular tachycardia

(VT) were divided into 2 groups: endocardial-alone ablation (Group 1, n=23) and endo-

epicardial ablation (Group 2, n=26). All patients had an implantable cardioverter defibrillator

(ICD). Conventional and 3D mappings were utilized to determine the mechanism of induced

VTs and to identify area of "scar" or “abnormal” myocardium. All critical sites responsible for

VTs and points with “abnormal” potential were targeted for ablation from endocardium (Group

1) or from both endocardium and epicardium (Group 2). Procedural endpoint was

noninducibility of sustained, monomorphic VT with isoproterenol. The presence of frequent

premature ventricular contractions (PVCs) at the end of ablation was recorded. Patients were

followed-up by ECGs, Holter and ICD interrogation. After a follow up of at least 3 years,

freedom from VAs or ICD therapy was 52.2% (12/23) in Group 1 and 84.6% (22/26) in Group 2

(p=0.029) with 21.7% (5/23) and 69.2% (18/26) patients off AAD (p<0.001), respectively.

Compared to patients with no PVC after ablation, patients with frequent PVCs after ablation

were more likely to have VA recurrence/ICD therapy [3/33, (9%) vs. 12/16 (75%), Log rank

p<0.001].

Conclusions - An endo-epicardial based ablation strategy achieves higher long-term freedom

from recurrent VAs off anti-arrhythmic therapy in patients with ARVD/C when compared to

endocardial-alone ablation. The presence of 10 PVCs per minute after ablation is associated

with more VA recurrence.

Key words: arrhythmogenic right ventricular dysplasia; cardiomyopathy; ventricular tachycardia; ablation; epicardial; premature ventricular contraction

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Introduction

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is characterized by

ventricular arrhythmias (VAs) or even sudden cardiac death (SCD) secondary to fibro-fatty

replacement of the right ventricular (RV) myocardium. It is a genetically determined myocardial

disease where the pathological lesions are believed to progress over time from the epicardium to

the endocardium and with diffuse involvement of the RV and the left ventricle (LV) in rare cases

[1,2]. Patients having recurrent sustained VT while on optimal pharmacological therapy are

candidates for catheter ablation. Even though the recent technological advances with

electroanatomic and voltage mapping systems have significantly improved the outcomes,

catheter ablation of ventricular tachycardia (VT) in ARVD/C patients is not considered curative

and has not been supported by the guideline as a first-line therapy [3-5]. However, only an

endocardial approach was used in most of the cases previously reported [3, 6-8]. We hypothesized

that the epicardial substrate may play an important role in the development of VT in patients

with ARVD/C and an ablation strategy including both endocardial and epicardial substrate

modification may be necessary to achieve better outcome. This multicenter study compared the

long-term freedom from VA in ARVD/C patients undergoing VT ablation by using either an

endocardial-alone or an endo-epicardial based approach. We also sought to identify the predictor

to ablation failure and recurrence of VA.

Methods

1. Study population

This is a prospective study including forty-nine (49) consecutive patients with ARVD/C

undergoing ablation of VTs at 7 centers in USA, Italy, Colombia and Canada. They were

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diagnosed with ARVD/C according to the Task Force Criteria [9, 10]. All patients had at least one

episode of symptomatic, sustained, monomorphic VT with left bundle branch block pattern

documented by ECG or Holter, with or without syncope. They all had received an implantable

cardioverter defibrillator (ICD) prior to the ablation but still suffered from recurrent VTs or

multiple ICD therapies despite anti-arrhythmic drugs (AAD) including sotalol, amiodarone,

dofetilide and beta-blockers. The study population was divided into 2 groups based on the

ablation strategy chosen by the ablating physician: in 23 patients (Group 1) ablation was

performed by an endocardial-alone approach; while 26 patients (Group 2) underwent an endo-

epicardial based ablation. Prior to the index procedure, 14 patients from Group 2 had one failed

endocardial ablation which had been performed at other centers using only standard activation

map of induced VT. They were referred to participating centers of the present study and did not

overlap with the patients in Group 1. The rest of the patients from Group 2 (N=12) underwent

endo-epicardial ablation as their primary procedures. All patients signed an informed consent for

catheter ablation of their VTs.

2. Electrophysiology Study and mapping

Patients were studied in the electrophysiology laboratory in the fasting state under conscious

sedation. Venous access was obtained from the groin veins. One quadripolar catheter and one

duo-decapolar catheter (St. Jude Medical Inc., Minneapolis, MI) were placed in the RV and

coronary sinus-right atrium, respectively. In patients in Group 2, subxiphoid epicardial access

was obtained by using fluoroscopic guidance as previously described [11].

Programmed stimulation including burst ventricular pacing and ramp pacing with up to 3

ventricular extrastimuli were delivered from 2 different RV sites in order to induce VA.

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Intravenous isoproterenol was also used (maximum dose 10μg/min) when necessary. Induced

VTs were compared with 12-lead ECGs of the clinical VT.

Endocardial mapping was performed in all patients while epicardial mapping was performed

once the epicardial space was accessed in Group 2 patients. Conventional mapping techniques

included pace mapping, activation mapping and entrainment mapping which helped

understanding the mechanism of the arrhythmias and identifying potential critical sites. The 3D

electroanatomic CARTO maps (Biosense Webster, Diamond Bar, CA), including the activation

and voltage map, were obtained in sinus rhythm and/or during hemodynamically-stable VT using

a 3.5mm open irrigated tip catheter (Biosense Webster, Diamond Bar, CA). Bipolar electrogram

signals were filtered at 30 to 400 Hz and were displayed on a real-time recording system. A fill

threshold < 15mm was used when CARTO map points were collected. Bipolar voltage

definitions of abnormal and normal myocardium were based on values validated previously in

both right and left ventricles [12, 13]. Endocardial regions with a bipolar electrogram amplitude

>1.5 mV were defined as “normal,” and “scar” is defined as those area with an amplitude <0.5

mV. “Abnormal” myocardium was defined as a region with a bipolar electrogram amplitude

between 0.5 and 1.5 mV. However, considering that overlying fat may result in voltage

attenuation of epicardial electrogram, the cut-off to define “normal” area of epicardium was set

as a bipolar electrogram amplitude > 1.0 mV while the “scar” myocardium was defined as a

bipolar electrogram amplitude < 0.5 mV. In addition to voltage criteria, “abnormal” electrogram

both in the endocardium and the epicardium included the delayed, split and fragmental

recordings [14]. The area of scar was measured by using the “area calculation” software included

in the CARTO system.

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3. Ablation strategy

In the index procedure, we intended to ablate not only the clinical VTs but all inducible,

sustained, monomorphic VTs at the time of electrophysiology study. Ablation was typically

performed with the 3.5mm open irrigated tip catheter. At each ablation point, radiofrequency

energy was applied for 60 to 120 seconds with a power output starting at 30 W and titrating up to

45 W with a maximum temperature limit of 41°C. In regions close to the phrenic nerve, high

output pacing (20 mA) was performed via the ablation catheter, and these locations were marked

on the electroanatomic map.

In general, our targets for ablation were:

(1) All points with “abnormal”, fractionated or delayed electrograms regardless of the location

within or around the scar area. In the epicardium, the endpoint was the elimination of these

potentials. In the endocardium, when we targeted low voltage potentials (bipolar voltage

amplitude 0.5-1.5mV) the endpoint was signal attenuation (bipolar voltage amplitude decreased

to <0.5mv); while when we targeted fragmented or delayed potentials with bipolar voltage

amplitude 0.5-1.5mV, the endpoint was the complete elimination of these potentials.

(2) Points those were critical in the initiation or maintenance of a VA (e.g. isthmus of a circuit or

a focal firing). If no specific foci/isthmus could be determined as the mechanism of the target

VTs or if the patients became hemodynamically unstable during the induced VTs, only substrate

ablation was performed to abolish all “abnormal” potentials. The specific ablation techniques

used in different groups were described below.

Group 1: Endocardial-alone ablation. Radiofrequency energy was delivered at specific sites

demonstrating “abnormal” voltage, isthmus of a circuit or arrhythmogenic foci. Under CARTO

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guidance, linear ablation lines were created to modify the endocardial substrate and were

designed to (1) connect scar/abnormal myocardium to valve continuity; (2) connect

scar/abnormal myocardium to another scar, or (3) encircle the scar/abnormal region, depending

on the scar location and size (Figure 1A-1B).

Group 2: Endo-epicardial ablation. An epicardial mapping and ablation was planned at the

beginning of the procedure rather than as a complimentary approach to an unsuccessful

endocardial ablation. Coronary angiogram was performed to confirm the absence of a coronary

artery at the ablation site based on the operator preference. At those specific sites suggestive of

“abnormal” myocardium on both endocardial and epicardial mapping, radiofrequency energy

was delivered from the endocardium and the opposite epicardial position to created transmural

lesions. At target sites demonstrating “abnormal” electrogram solely on the epicardial surface but

not on the endocardial mapping, ablation was delivered only in the epicardial space. In certain

cases, epicardial linear ablation was designed to encircle the entire scar/abnormal region and

composed with sequential point lesions along the boundary and within the scar area, with a goal

to eliminate/isolate all the “abnormal” recordings (Figure 1C-1D).

Programmed RV stimulation was repeated after completion of ablation. As before, up to 3

extrastimuli at 2 different RV sites were used to attempt to induce VT. If VT was still inducible,

additional ablation was performed following the strategy described previously. If the ablated

VTs or other sustained monomorphic VT could not be induced even with intravenous

isoproterenol infusion (up to 10μg/min), the procedure was considered successful. No further

ablation was performed when the only inducible arrhythmias were polymorphic VT/ventricular

fibrillation. After removing all the catheters from the ventricle, frequent spontaneous premature

ventricular contractions (PVCs) 10 beats/minute with/without isoproterenol provocation were

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recorded, but not targeted for additional ablation. All patients received screening for pericardial

effusion at the end of the procedure with echocardiography and fluoroscopy.

4. Follow-up

The patients were followed-up by their treating electrophysiologist. AADs were either

discontinued after ablation or maintained for 3 additional months and subsequently stopped.

Patients were routinely followed up in the outpatient clinic at 3, 6, and 12 months and then every

6 months thereafter when an ICD interrogation was performed to assess arrhythmia recurrence at

each office visit. AAD was resumed at physician’s discretion if recurrent VA was documented

by ECG, Holter or EGM retrieved from an ICD. Long term success was defined as a lack of

recurrence of sustained VT and/or appropriate ICD therapy.

5. Statistics

The data were prospectively collected. All continuous data are presented as mean +/- standard

deviation and were compared using student t-test or Wilcoxon rank-sum test where appropriate.

Categorical variables are described as count and percent and compared by using the Fisher’s

exact test. Since the ablation method was determined by the physicians at the participating

centers, it was necessary to test if difference in procedure assignment was not more frequent than

as predicted by chance alone. The Fleiss’s Kappa, an extension of Cohen's Kappa to evaluate

concordance between multiple raters, was utilized to assess the agreement in the choice of

ablation strategy among participating centers. Kaplan-Meier event-free survival analysis was

conducted to assess the cumulative freedom from VA recurrence/ICD therapy and log-rank test

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was used to compare recurrence between groups. A p value < 0.05 was considered statistically

significant. SAS 9.2 (SAS Institute Inc., Cary, NC) was used for statistical analysis.

Results

1. Patients.

Baseline clinical characteristics of the patients are summarized in Table 1. The demographics

were comparable between the two groups. All the patients had recurrent VT refractory to AADs

(Median 2, range 1-4) and underwent an ICD implant prior to the index ablation procedure. No

statistically significant bias was noted in the choice of procedure by physicians at the

participating centers (Fleiss’s Kappa=0.667; 95% CI 0.48-0.87, p= 0.001).

2. Electrophysiology study, mapping and ablation.

During the electrophysiology study, a median of 2 VTs (range from 1 to 4 in Group 1 and from 1

to 5 in Group 2) were induced and targeted for ablation. The procedure, fluoroscopy and

radiofrequency times were longer in Group 2 (Table 2).

CARTO map was successfully performed in all patients. Scar was identified in all patients with

predominant locations at the lateral tricuspid annulus, RV outflow tract, anterior or apical RV

wall and inferior RV wall. In Group 2 patients, the area of scar was larger in epicardium

(17.6±14.8 cm2) than that in endocardium (9.8±7.0cm2; Table 2, p=0.04; Figure 1C-1D).

All patients achieved the procedural endpoint at the end of ablation. Polymorphic VT/VF was

induced in 1 patient from Group 1 and 2 patients from Group 2, these tachycardias were not

targeted for further ablation. However, the presence of frequent PVCs after ablation was noted in

12 (52.1%) patients from Group 1 and 4 patients (15.4%) from Group 2 (p=0.006 vs. Group 1),

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respectively (Table 3). No tachycardia could be induced in these patients and the PVCs were not

subject to ablation in the index procedure.

3. Complications.

There were no major complications associated with the procedure in all patients. A groin

hematoma was noted in 2 patients in Group 1 and 1 patient in Group 2. No patient in Group 2

had symptomatic pericardial effusion/tamponade post ablation or at the time of discharge.

4. Follow-up.

No patient died or underwent heart transplantation during the follow-up period. After a follow-up

of at least 3 years (1224±310 days for Group 1 and 1175±112 days for Group 2), freedom from

VA or appropriate ICD therapy was 52.2% (12/23) in Group 1 and 84.6% (22/26) in Group 2,

respectively (Table 3). Among these patients, 5 from Group 1 (5/23, 21.7%) and 18 from Group

2 (18/26, 69.2%) were off AAD (p<0.001). Out of the 4 patients who had recurrence of VA in

Group 2, one patient had an ICD shock 2 weeks after the procedure, one had a VT treated with

anti-tachycardia pacing at 6 months follow up, and two had an ICD shock after one year when

discontinuing AADs. The Kaplan-Meier curve showed significant difference of arrhythmia/ICD

therapy-free survival between two groups (Log rank p=0.029, Figure 2).

Out of the 26 patients in Group 2, 14 (54%) had prior VT ablation at other centers from

endocardium before the index procedure. We performed a sub-analysis to examine if patients

with prior endocardial ablation had significantly different success rate compared to those

undergoing their first procedure. The event-free survival at the end of follow-up was 86% among

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patients with previous endocardial ablation and was 83% for those undergoing endo-epicardial

ablation as the first procedure (Log rank p=0.884).

At the end of the procedure, more patients in Group 1 presented with frequent PVCs than Group

2 (12/23 vs. 4/26, p=0.006; Table 3). More VA recurrence/ICD therapy were seen in patients

who had frequent PVCs after ablation (12/16, 75%) compared to patients in whom PVC was

absent (3/33, 9%; Log rank p<0.001; Table 3). In the overall study population (Figure 3A) or in

each separate group (Figure 3B-3C), patients who had no PVC after isoproterenol challenge at

the end of the procedure had higher VA/ICD therapy-free survival.

Discussions

The main findings of this study are: (1) compared to an endocardial-alone ablation strategy, an

endo-epicardial based approach increases long-term arrhythmia-free survival in patient with

ARVD/C; (2) the endo-epicardial ablation is more likely to result in discontinuation of AAD; (3)

at the end of the VT ablation procedure, the presence of frequent PVCs was associated with more

VA recurrence at follow up.

Arrhythmogenic right ventricular dysplasia/cardiomyopathy is a genetic, heterogeneous disorder

characterized by an autosomal dominant pattern of inheritance; and by histopathologic changes

of the myocardium which are believed to keep progressing. The disease process usually begins in

the subepicardium and progresses to the subendocardium, and rarely from RV to LV [15, 16]. The

clinical presentation of ARVD/C is variable and is thought to be related to the temporal

progression of the pathologic lesions. Accordingly, ARVD/C patients are classified into four

clinico-pathologic stages: “Concealed Phase or Silent Phase”, “overt arrhythmic phase”, “global

right ventricular dysfunctional phase” and “bi-ventricular pump failure phase” [17]. However,

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mostly commonly, patients with ARVD/C come to clinical attention owing to the development

of symptomatic VA with RV origin, usually at the age of 30-40 years and precipitated by

exercise. This subgroup of ARVD/C patients mostly remained in the second stage of the disease

and constituted the majority who seek treatment for their arrhythmias rather than heart failure. At

this time, the disease is characterized by segmental or global RV pathological changes with

residual normal myocardium located in the endocardium, rarely associated with histological

evidence of LV involvement [15-19]. The regional (between “normal’ and “scar/abnormal” areas)

and transmural (between epicardium, mid-layer myocardium and endocardium)

electrophysiological heterogeneities provide the arrhythmogenic substrate which are the targets

of ablation in ARVD/C patients [20]. In light of this, one would expect that a combined endo-

epicardial ablation approach would achieve higher freedom from recurrent arrhythmias.

Radiofrequency ablation of VA has traditionally only been used in medically refractory

ARVD/C cases due to fear of perforation of the thin right ventricular wall and the progressive

nature of the disease [5]. With the currently available techniques, catheter ablation has become a

therapeutic option in ARVD/C patients with recurrent VA, as AAD have not clearly proven to be

effective and ICD implantation itself is not curative. However, most of procedures in the

published series were performed using an endocardial approach and the ablation success rate was

not satisfactory [3-8, 21-23]. Epicardial ablation has been recently applied in ARVD/C patients and

associated with better arrhythmia control, but under most circumstance, this technique was used

as a complimentary approach to previous single or multiple failed endocardial-alone ablations [14,

24, 25]. Of note, the initial experience on non-pharmacologic therapy of refractory VT in ARVD/C

came from surgeons who either made epicardial incision or placed surgical ablation at the site of

origin of VT, which successfully prevented the recurrence of arrhythmias [26, 27]. Several

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mechanisms may explain the uniform outcome of endocardial-alone ablation and the necessity of

performing endo-epicardial based ablation in ARVD/C patients. First, parts of the RV wall may

have become thickened in some ARVD/C patients and RF energy delivered from the

endocardium alone is unable to achieve transmural lesions [14]. To this aspect, the endo-epicardial

ablation is more likely to create full-thickness permanent myocardial necrosis and eliminate the

arrhythmogenic sources including intramural phase 2 reentry. Second, the specific target of

ablation based on endocardial mapping (i.e. exit of a reentry circuit or a focal pattern activation)

could be just the breakout site of a reentry circuit that is located in the epicardium. Therefore, the

tachycardia can only be abolished by RF ablation in the epicardial space. Furthermore, it has

been noted that the epicardial scar/abnormal region identified by 3D voltage mapping many

times extends beyond the site of the endocardial scar/abnormal areas [14, 28], suggesting that parts

of the epicardial arrhythmogenic substrate would never be targeted and modified by extensive

endocardial-alone ablation. Our approach used in Group 2 patients included linear ablation

encircling the epicardial scar/abnormal area and abolition of any delayed, split, and fragmented

“abnormal” electrograms. By this way, potential arrhythmogenic sources localized within this

zone were isolated or abolished and possible reentrant circuits located in the scar border zone

were also eliminated. Similar technique was recently reported by Bakir I. et al [29] who used cryo

energy in a surgical ablation procedure in an ARVD/C patient with incessant VT despite 3

endocardial ablations; and by Garcia FC. et al [14] who reported their experience on epicardial

ablation in patients with previously failed endocardial procedures.

It has been recognized that the fat tissue in the pericardial space may influence the human

epicardial bipolar electrogram recordings by which an ablation target is determined [30, 31].

However, the fat pad will only decrease the amplitude of the electrogram if it is overlying an area

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of normal myocardial, but will not make the electrogram becoming delayed, split or fragmental

which are characteristics of diseased myocardium. Looking at the amplitude, timing and

morphology of the epicardial electrogram we were able to accurately detect the boundary of

“abnormal/scar” region and distinguish it from normal myocardium. This is consistent with the

findings during LV epicardial mapping [28].

Even though reentry is the main mechanism of VT in ARVD/C, enhanced automaticity occurring

during exercise and trigged activity from inflammatory myocytes may also contribute to the

development of VA. When reentrant circuit was present, PVCs associated with trigger activity

could initiate sustained reentry tachycardia. In addition, after all existing reentrant circuits are

ablated, enhanced automaticity could initiate focal tachycardia [20]. On the other hand, due to the

progressive nature of ARVD/C, new reentrant circuit may become manifested. This could

explain why the presence of frequent PVCs after VT ablation was associated with higher

recurrence of arrhythmia in ARVD/C patients. Whether these PVCs should be targeted for

ablation in order to further improve procedure success remained unclear and warrant additional

studies.

Study limitations

This was not a randomized study but consecutive patients were enrolled in different centers.

There could have been potential biases in selecting the ablation strategy for the patients.

However, our subgroup analysis showed no inter-center difference in choice of procedure and no

outcome difference between patients with and without previous endocardial ablation within

Group 2. This made it less likely that non-randomization bias had significant influence on our

results. Given the small number of events, we could not perform multivariable Cox analysis with

existing reenttrararararararan

0]. OnOnOnOnOnOnO t ttttthehehehehehehe oo o o o oothththththththerereeeee h

T

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h a

f ARVD/C, new reentrant circuit may become manifested. T

sence of frequent PVCs after VT ablation was associated wit

hmia in ARVD/C patients. Whether these PVCs should be ta



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15

the current population, which might not have sufficient power to show independent predictor(s).

Biopsy and genetic testing were not available in all patients, but ARVD/C was diagnosed

according to the consensus document criteria.

Conclusion

Epicardial scar and abnormality play an important role in the development of VAs in ARVD/C.

An ablation strategy based on substrate modification with simultaneous endocardial and

epicardial RF energy delivery is associated with improved arrhythmia-free survival and higher

probability of AAD discontinuation. This approach should be considered as the initial strategy

of VT ablation in patients with ARVD/C. The presence of 10 PVCs per minute after ablation is

associated with more VA recurrence.

Funding Sources: Dr. Bai was supported from China by the Program for New Century Excellent Talents in University (NCET-09-0376); the National Natural Science Foundation (NSFC-30700297 and 30973601) and the Scientific Research Foundation for the Returned Overseas Chinese Scholars (SFR ROCS 2008-101).

Conflict of Interest Disclosures: Preliminary results of this study were presented as an abstract at the European Cardiology Society Scientific Session 2010 and the American Heart Association Scientific Session 2010. Dr. Di Biase is a consultant for Hansen Medical and Biosense Webster. Dr. Natale received speaker honorariums from Boston Scientific, Biosense Webster, St. Jude Medical, Biotronik and Life Watch.

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Table 1. Baseline Characteristics of Study Subjects

Group 1 (N=23) Group 2 (N=26) P value

Age (years)† 34±14 37±11 0.47

Male (%) 15 (65%) 18 (69%) 0.76

LV ejection fraction (%)† 57±7 53±10 0.32

Failed AAD prior to index ablation

Sotalol 11(47.8%) 13 (50%) 1.00

Amiodarone 17(73.9%) 18 (73.1%) 0.72

Dofetilide 1 (4.3%) 2 (7.7%) 1.00

Beta blocker 4 (17.4) 5 (19.2%) 0.97

Class I and other AADs 7 (30.4%) 6 (23.1%) 0.56

AAD: anti-arrhythmic drug; LV: left ventricular

†: The numbers represent mean +/- standard deviation.

11

15 (65%) 18 (69%)

(%)† 57±7 53±10

index



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Table 2. Comparison of Procedural Parameters between Two Groups

Group 1 (N=23) Group 2 (N=26) P value VT targeted for ablation‡ 2 (1-4) 2 (1-5) 0.69 Cycle length of VTs (ms) 262±62 287±57 0.85 Endocardial CARTO map points 316±127 356±143 0.87 Epicardial CARTO map points N/A 334±123 N/A Endocardial scar area (cm2) 10.9±6.4 9.8±7.0 0.51 Epicardial scar area (cm2) N/A 17.6±14.8* N/A Procedure time (hour) 3.9±1.1 5.3±1.2 0.008 Fluoroscopy time (minute) 51.3±20.2 65.9±13.1 0.015 Radiofrequency time (minute) 20.2±15.3 25.8±13.7 0.036 *: p=0.04 compared to endocardial scar area in Group 2 patients. VT: ventricular tachycardia ‡ The numbers represent median (range). The rest of numbers provided in the table represent mean +/- standard deviation.

Table 3. Prevalence of PVC and Recurrence of VA in Two Groups

Presence of frequent PVC

with/without Isoproterenol Absence of PVC with Isoproterenol

Group

Total

No VA

Recurrence/IC

D Therapy

VA

Recurrence/IC

D Therapy

Tota

l

No VA

Recurrence/IC

D Therapy

VA

Recurrence/IC

D Therapy

Group 1

(N=23)12 3 (25%) 9 (75%) 11 9 (82%) 2 (18%)

Group 2

(N=26)4 1 (25%) 3 (75%) 22 21 (94%) 1 (6%)

Total (N=49) 16 4 (25%) 12 (75%) 33 30 (91%) 3 (9%)

PVC: premature ventricular contraction; VA: ventricular arrhythmia; ICD: implantable cardioverter-defibrillator

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21

Figure Legends:

Figure 1 A-B. Bipolar voltage map of the RV endocardium in a patient with ARVD/C from

Group 1 (A: LAO view; B: AP view). Regions in red represent scar (bipolar voltage <0.5 mV),

and purple regions represent normal myocardium (bipolar voltage >1.5 mV). Other colored

regions represent abnormal myocardial regions (bipolar voltage between 0.5 and 1.0 mV). The

scar is located in superior anterior RV and proximal RV outflow tract. In this case, serial

ablations were applied (red dots) inside scar region and to surround region of abnormal voltage.

RV: right ventricular; ARVD/C: arrhythmogenic right ventricular dysplasia/cardiomyopathy.

Figure 1 C-D. Endocardial (C: AP view) and epicardial (D: AP view) bipolar voltage map of

the RV in a patient with ARVD/C from Group 2. Definitions of endocardial scar or normal

myocardium remained the same as in Figure 1A and 1B. Epicardially, “normal” area was set as a

bipolar electrogram amplitude > 1.0 mV while the “scar” myocardium was defined as a bipolar

electrogram amplitude < 0.5 mV. EGMs of representative endocardial/epicardial mapping site

were shown in the middle panel. In each EGM recording, in addition to ECG leads II, V3 and

aVL, electrograms on proximal (M3-M4) and distal (M1-M2) ablation catheter were shown. The

scar region was larger in the epicardium, and it was located in anterior and lateral RV extending

to the basal RV and tricuspid valve area. In addition to lesions (red dots) placed at opposite

endocardial and epicardial sites with abnormal voltage, more RF applications were applied in the

epicardium at sites demonstrating abnormal recordings. EGM: electrogram.

Figure 2. Ventricular arrhythmia/ICD therapy-free survival by the ablation approach.

The Kaplan-Meier curve showed significant difference of ventricular arrhythmia/ICD therapy-

free survival between Group 1 (Endocardial-alone ablation) and Group 2 (Endo-epicardial

ablation). ICD: implantable cardioverter defibrillator; VA: ventricular arrhythmia.

Figure 3. Ventricular arrhythmia/ICD therapy-free survival by the presence of frequent PVCs in

the entire study population (A) and in Group 1 (B) or Group 2 (C). Regardless of the ablation

approach, the presence of frequent PVCs at the end of ablation was associated with more VA

recurrence. PVC: premature ventricular contraction; VA: ventricular arrhythmia

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de < 0.5 mV. EGMs of representative endocardial/epicardia

middle panel. In each EGM recording, in addition to ECG lea

on proximal (M3-M4) and distal (M1-M2) ablation catheter w

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Pelargonio, Pietro Santarelli, Javier Sanchez, Claudio Tondo and Andrea NataleDavid Burkhardt, Richard Hongo, Salwa Beheiry, Antonio Dello Russo, Michela Casella, Gemma

Santangeli, Luis Carlos Saenz, Miguel Vacca, Atul Verma, Yariv Khaykin, Sanghamitra Mohanty, J. Rong Bai, Luigi Di Biase, Kalyanam Shivkumar, Prasant Mohanty, Roderick Tung, Pasquale

Mapping and AblationDysplasia/Cardiomyopathy: Arrhythmia-Free Survival after Endo-Epicardial Substrate Based

Ablation of Ventricular Arrhythmias in Arrhythmogenic Right Ventricular

Print ISSN: 1941-3149. Online ISSN: 1941-3084 Copyright © 2011 American Heart Association, Inc. All rights reserved.

Dallas, TX 75231is published by the American Heart Association, 7272 Greenville Avenue,Circulation: Arrhythmia and Electrophysiology

published online June 10, 2011;Circ Arrhythm Electrophysiol.

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