Three-Dimensional Electroanatomical Voltage Mapping and Histologic Evaluation of Myocardial Substrate in Right Ventricular Outflow Tract Tachycardia

Journal of the American College of Cardiology © 2008 by the American College of Cardiology Foundation Published by Elsevier Inc.

Vol. 51, No. 7, 2008 ISSN 0735-1097/08/$34.00 doi:10.1016/j.jacc.2007.11.027

Heart Rhythm Disorders

Three-Dimensional Electroanatomical Voltage Mapping and Histologic Evaluation of Myocardial Substrate in Right Ventricular Outflow Tract Tachycardia Domenico Corrado, MD, PHD,* Cristina Basso, MD, PHD,† Loira Leoni, MD, PHD,* Barbara Tokajuk, MD, PHD,* Pietro Turrini, MD, PHD,* Barbara Bauce, MD, PHD,* Federico Migliore, MD,* Andrea Pavei, MD,* Giuseppe Tarantini, MD, PHD,* Massimo Napodano, MD,* Angelo Ramondo, MD,* Gianfranco Buja, MD,* Sabino Iliceto, MD,* Gaetano Thiene, MD† Padua, Italy Objectives

We tested whether 3-dimensional electroanatomical voltage mapping (EVM) may help in the differential diagnosis between idiopathic right ventricular outflow tract (RVOT) tachycardia and arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D).

Background

Right ventricular EVM has been demonstrated to reliably identify low-voltage regions (“electroanatomical scar”), which in patients with ARVC/D correspond to areas of fibrofatty myocardial replacement.

Methods

The study population comprised 27 patients (15 men and 12 women, age 33.9 ⫾ 8 years) with RVOT tachycardia and no echocardiographic/angiographic evidence of right ventricular (RV) dilation/dysfunction, who underwent EVM and endomyocardial biopsy (EMB) for characterization of ventricular tachycardia (VT) substrate before catheter ablation.

Results

Electroanatomical voltage mapping was normal in 20 of 27 patients (74%, group A), with electrogram voltage ⬎1.5 mV throughout the RV. The other 7 patients (26%, group B) showed ⱖ1 (1.4 ⫾ 07) RV electroanatomical scar area(s) (bipolar voltage ⬍0.5 mV) that correlated with fibrofatty myocardial replacement at EMB (p ⬍ 0.001). Clinical predictors of RV scar were right precordial QRS prolongation (p ⬍ 0.001) and VT inducibility (p ⫽ 0.001). Catheter ablation successfully eliminated VT in 18 of 20 patients (90%). During a follow-up of 41 ⫾ 8 months, 3 of 7 patients (43%) from group B received an implantable defibrillator because of life-threatening ventricular arrhythmias, compared with no patients from group A (p ⫽ 0.016).

Conclusions

An early/minor form of ARVC/D may mimic idiopathic RVOT tachycardia. Electroanatomical voltage mapping is able to identify RVOT tachycardia due to concealed ARVC/D by detecting RVOT electroanatomical scars that correlate with fibrofatty myocardial replacement at EMB and predispose to sudden arrhythmic death. (J Am Coll Cardiol 2008;51:731–9) © 2008 by the American College of Cardiology Foundation

The right ventricular outflow tract (RVOT) is the most common source of nonischemic ventricular tachycardia (VT). Right ventricular outflow tract tachycardia is commonly due to idiopathic RVOT tachycardia or arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) (1). Idiopathic RVOT tachycardia is a nonfamilial and benign condition that occurs in young individuals without

From the Departments of *Cardiac, Thoracic, and Vascular Sciences, and †MedicalDiagnostic Sciences, University of Padua Medical School, Padua, Italy. This study was supported by the Ministry of Health, Rome, Italy; the CARIPARO Foundation, Padua, Italy; the Veneto Region, Venice, Italy; and the European Community research contract # QLG1 CT-2000 01091. Manuscript received June 11, 2007; revised manuscript received October 24, 2007, accepted November 8, 2007.

structural heart disease (1,2). On the other hand, ARVC/D is a progressive, often inherited, cardiomyopathy characterized by right ventricular (RV) dysfunction due to fibrofatty See page 740

replacement of myocardium, which predisposes to ventricular arrhythmias and sudden arrhythmic death, especially in young people and athletes (3–5). Although RVOT tachycardia is considered benign and not progressive, it may cause syncope and, uncommonly, sudden cardiac death (6 –9). These rare malignant events are most likely explained by the clinical overlap between idiopathic RVOT tachycardia and early and/or segmental ARVC/D. Therefore, distinction

732

Corrado et al. RVOT Tachycardia

between patients with idiopathic RVOT tachycardia and ARVC/D is critical because it implies differARVC/D ⴝ arrhythmogenic ent prognosis and management right ventricular strategies. Differential diagnosis, cardiomyopathy/dysplasia however, may be challenging, esCMR ⴝ cardiac magnetic resonance pecially in patients with ARVC/D at its early stage or in its minor EMB ⴝ endomyocardial biopsy variant, which is characterized by EVM ⴝ electroanatomical clinically subtle myocardial abnorvoltage mapping malities without evidence of LV ⴝ left ventricular dilation/dysfunction ventricle/ventricular (1,4,5,10). RV ⴝ right The hallmark pathological ventricle/ventricular lesion of ARVC/D is the transRVOT ⴝ right ventricular mural loss of the myocardium outflow tract of the RV free wall with reSAECG ⴝ signal-averaged placement by fibrofatty tissue electrocardiogram (3–5). Three-dimensional electroVT ⴝ ventricular anatomical voltage mapping (EVM) tachycardia by CARTO system (BiosenseWebster, Diamond Bar, California) has been demonstrated to reliably identify and characterize low-voltage regions (“electroanatomical scar”) (11– 14), which in patients with ARVC/D correspond to areas of myocardial depletion and correlate with the histopathological finding of myocardial atrophy and fibrofatty replacement at endomyocardial biopsy (EMB) (13). The aim of the present study was to test whether EVM may help in the differential diagnosis between idiopathic and ARVC/D-related RVOT tachycardia by the identification of otherwise concealed cardiomyopathic changes in patients presenting with RVOT tachycardia and an apparently normal heart. Abbreviations and Acronyms

Methods Among 89 consecutive patients with RVOT tachycardia (defined as monomorphic left bundle branch block pattern and inferior axis) and an apparently normal heart who were referred for catheter ablation between 2002 and 2005, 27 (30%) underwent EVM and EMB to exclude an underlying subtle ARVC/D (see the following text) and are the subject of this study. The study was approved by the institutional review board, and all patients gave their informed consent. Clinical evaluation. In all patients cardiovascular evaluation included history, physical examination, laboratory tests, chest radiograph, 12-lead electrocardiogram (ECG) recording, 24-h Holter monitoring, signal averagedelectrocardiogram (SAECG), exercise testing, 2-dimensional/color Doppler echocardiography, RV and left ventricular (LV) cineagiography (in the right and left anterior oblique views), and coronary angiography. Technical equipment, protocols, and reference values of each investigation have been reported in detail elsewhere (13). Quantitative RV echocardiographic measurements were performed and

JACC Vol. 51, No. 7, 2008 February 19, 2008:731–9

evaluated according to Yoerger et al. (15). Patients were judged as having a structurally normal heart on the basis of normal RV and LV cavity dimension and function, either global or regional, as determined by echocardiography and cardiac catheterization. No patients fulfilled the diagnostic criteria for ARVC/D recommended by the European Society of Cardiology/International Society and Federation of Cardiology Task Force (16). Characterization of VT myocardial substrate. Although the study patients had normal RV and LV cavity dimension and function, they underwent further evaluation through EVM and EMB because of 1 or more of the following clinical findings: family history of sudden death (n ⫽ 3), pre-syncope (n ⫽ 7), competitive athletic activity (n ⫽ 9), QRS duration ⱖ110 ms in right precordial leads (n ⫽ 6), late potentials at SAECG (n ⫽ 6), and inverted T waves in inferior leads (n ⫽ 4). EVM. All patients underwent detailed EVM by the CARTO system (Biosense-Webster) during sinus rhythm, as previously reported (11–14). In brief, a 7-F Navi-Star (Biosense-Webster) catheter, with a 4-mm distal tip electrode and a 2-mm ring electrode with an interelectrode distance of 1 mm, was introduced into the RV under fluoroscopic guidance and used as the mapping/ablation catheter. The catheter was placed at multiple sites on the endocardial surface to record bipolar electrograms from RV inflow, anterior free wall, apex, and outflow. Bipolar electrogram signals (filtered at 10 to 400 Hz and displayed at 100 mm/s speeds on the CARTO system) were analyzed with regard to amplitude, duration, relation to the surface QRS, and presence of multiple components. A recording was accepted and integrated into the map when the variability in cycle length, local activation time stability, and maximum beat-to-beat difference of the location of the catheter were ⬍2%, ⬍3 ms, and ⬍4 mm, respectively. These parameters, combined with impedence measurements, were used to exclude signals with low amplitude due to poor endocardial catheter contact. In addition, adequate catheter contact was confirmed by concordant catheter tip motion with the cardiac silhouettes on fluoroscopy. Bipolar voltage reference for normal and abnormal myocardium was based on values validated by intraoperative and catheter mapping (17,18) and used in previous voltage mapping studies (12–14,19,20). The color display for depicting normal and abnormal voltage myocardium ranged from “red” representing “electroanatomical scar tissue” (amplitude ⬍0.5 mV) to “purple” representing “electroanatomical normal tissue” (amplitude ⱖ1.5 mV). Intermediate colors represented the “electroanatomical border zone” (signal amplitudes between 0.5 and 1.5 mV). Complete endocardial maps were obtained in all patients to ensure reconstruction of a 3-dimensional geometry of the RV chamber and to identify scar regions. Regions showing low-amplitude electrograms were mapped with greater point density to delineate the extent and borders of “electroanatomical scar” areas.

Corrado et al. RVOT Tachycardia

JACC Vol. 51, No. 7, 2008 February 19, 2008:731–9

EMB. All patients underwent EMB of the RV via the femoral vein using the long sheath technique (Disposable Cordis Bioptome, Miami, Florida). The samples were obtained under fluoroscopic guidance from the anterior RV free wall toward the ventricular septum (13,21), blindly of EVM results. Biopsy specimens were fixed in 10% phosphatebuffered formalin (pH 7.35) and processed for histologic examination. Seven-micron-thick paraffin-embedded sections were serially cut and stained according to the hematoxylineosin and Heidenhain trichrome techniques. A mean of 2.9 ⫾ 0.7 EMB samples per patient were available for investigation. Histopathological diagnosis of ARVC/D was put forward independently by 2 observers (C.B., G.T.), blinded to EVM results, on the basis of a significant amount of myocardial atrophy and fibrofatty tissue replacement, which was evaluated through histomorphometric analysis (21). Electrophysiological study and catheter ablation. All antiarrhythmic drugs were discontinued 5 half-lives (6 weeks for amiodarone) before the electrophysiological study. Programmed ventricular stimulation protocol included 3 drivecycle lengths (600, 500, and 400 ms) and 3 ventricular extrastimuli while pacing from 2 RV sites (apex and outflow tract). In patients in whom VT was not inducible at baseline, isoproterenol was administrated intravenously (2 to 6 ␮g/min) and titrated so that the clinical VT or repetitive monomorphic ventricular beats matching the clinical VT morphology occurred. The site of origin of the ventricular arrhythmia was established by activation mapping and/or pace mapping. The activation map was created by mapping several points within the RVOT during ventricular arrhythmias while using a surface ECG lead as a reference. Activation times were assigned on the basis of the onset of bipolar electrograms and displayed as color gradients on a 3-dimensional activation map. A suitable target for ablation was selected based on the earliest endocardial activation times during arrhythmia (or during episodes of frequent premature ventricular beats with QRS morphology identical to the clinical tachycardia) and confirmed by the pace mapping that provided ⱖ11 of 12 matches between paced and spontaneous QRS complexes.

733

Sustained VTs inducible by programmed ventricular stimulation were entrained at cycle lengths of 20 to 40 ms below the cycle length of the tachycardia to guide the site of ablation. Substrate-based catheter ablation at sinus rhythm was accomplished by creating linear ablation lesions encircling and/or connecting RVOT electroanatomical scars, according to a previously reported method (12,14). Ablation was performed with a 4-mm tip ablation catheter using radiofrequency energy (target temperature 60°C, maximal power 50 W) delivered for up to 60 s. The procedure was considered acutely successful if ventricular arrhythmia was abolished during ablation, remained absent for at least 30 min after ablation, and was not reinduced by either programmed ventricular stimulation or isoproterenol infusion. Statistical analysis. Continuous variables are expressed as range and mean ⫾ standard deviation. Categorical differences between groups were evaluated by the Fisher exact text. Differences between group means were compared by unpaired t test. All probability values reported are 2-sided, and a probability value ⬍0.05 was considered to be statistically significant. Results Clinical characteristics. Clinical characteristics, instrumental findings, and electrophysiological data are summarized in Tables 1 to 3. The study population consisted of 27 patients (15 men and 12 women; age range 16 to 51 years; mean age 33.9 ⫾ 8 years), 9 of whom were competitive athletes. Three patients had a family history of premature (age ⬍40 years) sudden death. Spontaneous ventricular arrhythmias with a left bundle branch block/inferior axis pattern were documented in all patients and included sustained monomorphic VT in 17 (Figs. 1 and 2) and nonsustained VT in 10. All 27 patients had normal LV and RV size and function, either global or regional, by echocardiography and angiography (Table 1). Seven patients underwent cardiac magnetic resonance (CMR) as part of the initial clinical evaluation at their local hospital; 4 of these (57%) were reported to have abnormal findings consistent with a diagnosis of ARVC/D. In 6 of 27 patients (22%), EMB showed significant myocardial atrophy and fibrofatty

Clinical Characteristics of the Overall Sample and According to Results of Voltage Mapping Table 1

Clinical Characteristics of the Overall Sample and According to Results of Voltage Mapping

Clinical Characteristics Age (yrs) Gender (male) Family history of sudden death

Overall Sample (n ⴝ 27)

Normal EVM Group A (n ⴝ 20)

Abnormal EVM Group B (n ⴝ 7)

33.9 ⫾ 8

33.6 ⫾ 6

34.1 ⫾ 3

0.91

12 (60)

3 (43)

0.66

15 (55)

p Value

3 (11)

2 (10)

1 (14)

1.0

25 (92)

19 (88)

6 (86)

0.46

Pre-syncope

7 (26)

4/19 (21)

3/6 (50)

0.30

Palpitations

18 (72)

15/19 (79)

3/6 (50)

0.30

Competitive athletes

9 (33)

7 (35)

2 (28)

1.0

Interval between symptom onset and EVM (months)

35 ⫾ 8

36 ⫾ 4

0.9

Clinical symptoms

Values are expressed as n (%) or mean ⫾ SD. EVM ⫽ electroanatomical voltage mapping.

35 ⫾ 9

734

Corrado et al. RVOT Tachycardia

JACC Vol. 51, No. 7, 2008 February 19, 2008:731–9

Instrumental Findings of the Overall Sample and According to Results of Voltage Mapping Table 2

Instrumental Findings of the Overall Sample and According to Results of Voltage Mapping Overall Sample (n ⴝ 27)

Normal EVM Group A (n ⴝ 20)

Abnormal EVM Group B (n ⴝ 7)

p Value

Depolarization/conduction ECG abnormalities QRS duration ⱖ110 ms (V1 to V2)

6 (22)

1 (5)

5 (71)

0.001

Late potential on SAECG

7 (26)

3 (15)

4 (57)

0.05

Repolarization abnormalities 0

Inverted T waves in V1 to V2/V3 Inverted T waves in inferior leads

0

0 2 (28)

—

4 (15)

2 (10)

0.27

Sustained VT

17 (63)

12 (60)

5 (71)

0.68

Nonsustained VT

10 (27)

8 (40)

2 (29)

0.68 0.08

Ventricular arrhythmias

Lead I QRS duration ⱖ120 ms during VT

14 (52)

8 (40)

6 (86)

4/7 (57)

3/5 (60)

1/2 (50)

1.0

Echocardiographic RVEDA (cm2)

16.5 ⫾ 2.1

16.3 ⫾ 2.1

16.9 ⫾ 2.2

0.52

Echocardiographic RVOT-PLAX diastole (mm)

26.8 ⫾ 2.7

26.7 ⫾ 2.7

27.1 ⫾ 2.9

0.74

Abnormal CMR Echocardiographic findings

Angiographic findings Angiographic RV ejection fraction

61 ⫾ 9

62 ⫾ 4

61 ⫾ 7

0.74

Angiographic RVED volume (ml/m2)

59 ⫾ 8

59 ⫾ 1

60 ⫾ 6

0.67

Fibrofatty myocardial replacement at EMB

6 (22)

0

6 (86)

⬍0.001

Values are expressed as n (%) or mean ⫾ SD. CMR ⫽ cardiac magnetic resonance; ECG ⫽ electrocardiogram; EMB ⫽ endomyocardial biopsy; EVM ⫽ electroanatomical voltage mapping; PLAX ⫽ parasternal long axis; RV ⫽ right ventricular; RVED ⫽ right ventricular end-diastolic; RVEDA ⫽ right ventricular end-diastolic area; RVOT ⫽ right ventricular outflow tract; SAECG ⫽ signal-averaged electrocardiogram; VT ⫽ ventricular tachycardia.

replacement consistent with ARVC/D; in the remaining 21 patients (78%), no histologic abnormalities, either inflammatory or degenerative, were found, and the EMB was reported as normal (Figs. 1 and 2). EVM. Electroanatomical voltage mapping was successfully acquired during sinus rhythm in all patients. The mean number of sites sampled in RV EVM was 187 ⫾ 29, with an average mapping period of 28 ⫾ 7 min. Electroanatomical voltage mapping was normal in 20 patients (74%) (group A), with preserved bipolar electrogram amplitude (5.1 ⫾ 0.8 mV) and duration (36.9 ⫾ 6 ms) throughout the RV free wall and septum (Fig. 1). The remaining 7 patients (26%) had an abnormal RV EVM (group B) showing ⱖ1 area (mean 1.4 ⫾ 0.7), with bipolar electrogram voltage ⬍0.5 mV (i.e., electroanatomical scar tissue) (Fig. 2). Lowvoltage areas were sharply demarcated by a border zone with

reduced signal amplitudes (0.5 to 1.5 mV), which merged into normal myocardium (⬎1.5 mV). Compared with electrograms sampled from unaffected areas, those recorded from within electroanatomical scar tissue showed lower amplitude (0.3 ⫾ 0.09 mV vs. 4.7 ⫾ 0.6 mV) and prolonged duration (76.7 ⫾ 18 ms vs. 37.3 ⫾ 8 ms; p ⬍ 0.001) and extended beyond the offset of the surface QRS (66%; p ⬍ 0.001). In 5 patients the electroanatomical scars were confined to the anteroinfundibular region, whereas in the remaining 2 patients there were multiregional RV lesions, which also involved areas remote to RVOT such as the inferobasal (2 patients) and the apical (1 patient) regions. The ventricular septum was spared in all patients. Electrophysiological studies and catheter ablation. Clinical arrhythmia was reproduced in the electrophysiological laboratory in all patients. Programmed ventricular stimulation

Electrophysiological Findings of the Overall Sample and According to Results of Voltage Mapping Table 3

Electrophysiological Findings of the Overall Sample and According to Results of Voltage Mapping Overall Sample (n ⴝ 27)

Normal EVM Group A (n ⴝ 20)

Abnormal EVM Group B (n ⴝ 7)

p Value

Programmed ventricular stimulation VT inducibility Number of VT morphologies Earliest endocardial activation of ventricular arrhythmias in the nonseptal surface of RVOT

6 (22)

1 (5)

1.3 ⫾ 0.5

1⫾0

12 (44)

5 (71)

0.001

1.4 ⫾ 0.5

0.17

6 (30)

6 (86)

0.024

VT cycle length (mean) (ms)

353 ⫾ 68

358 ⫾ 54

346 ⫾ 61

0.36

Acute success of catheter ablation

18/20 (90)

14/15 (93)

4/5 (80)

0.45

41 ⫾ 8

41 ⫾ 5

Follow-up after mapping/ablation (months) VT relapses ICD therapy (during follow-up) Values are expressed as n (%) or mean ⫾ SD. ICD ⫽ implantable cardioverter-defibrillator; other abbreviations as in Table 2.

10/27 (37) 3 (11)

42 ⫾ 13

0.74

7 (35)

3 (43)

1.0

0

3 (43)

0.012

Corrado et al. RVOT Tachycardia

JACC Vol. 51, No. 7, 2008 February 19, 2008:731–9

735

patients with inducible and tolerated sustained VT, the arrhythmia circuit was initially localized and ablated by activation/entrainment mapping during VT. In 3 of these patients, in whom sustained VT remained inducible after electrophysiological mapping-guided ablation, an alternative substrate-based ablation approach was attempted at sinus rhythm by isolating RVOT electroanatomical scars and connecting scar to scar and/or scar to the pulmonary valve annulus (Fig. 3). A mean of 23 ⫾ 18 radiofrequency lesions was applied per patient. Acute success was achieved in 18 of 20 (90%) patients. During a mean follow-up period of 41 ⫾ 8 months, 17 of 27 patients remained free of VT. Ventricular tachycardia recurrence was documented in the remaining 10 patients: in 3 of 18 (17%) patients with successful catheter ablation and in 7 of 9 patients (78%) either not undergoing catheter ablation (5 of 7, 71%) or undergoing an unsuccessful procedure (2 of 2, 100%). Three patients received an implantable defibrillator because of life-threatening VT leading to either syncope (2 patients) or aborted sudden death (1 patient). The other 7 patients experienced hemo-

Figure 1

Electrocardiographic and Histopathological Findings in a Representative Patient From Group A

(A) Right anterior oblique view of the right ventricular (RV) bipolar voltage map showing preserved bipolar voltages values (purple indicates ⬎1.5 mV) throughout the RV. (B) Endomyocardial biopsy sample showing normal myocardium (Heidenhain trichrome ⫻40). (C) 12-lead electrocardiogram during clinicallysustained ventricular tachycardia 170 beats/min, with a left bundle branch block/inferior axis morphology.

induced 1 or more sustained VT in 6 patients: overall 8 induced morphologies with at least 1 identical to that recorded clinically. In the remaining 21 patients, clinical arrhythmia was produced or worsened by isoproterenol challenge: 9 patients had isolated or coupled monomorphic premature ventricular beats, 8 had nonsustained VT, and 4 had sustained VT, which in each case matched the clinical VT morphology. Mean cycle length during VT was 353 ⫾ 68 ms (range 240 to 470 ms). Activation mapping and/or pace mapping showed that ventricular arrhythmia arose from the RVOT in each case: anteroseptally in 12, anterolaterally in 9, posterolaterally in 3, midposteroseptally in 2, and close to the His bundle in 1. In all patients from group B, the best VT pace map was obtained from the RVOT sites of electroanatomical scars. Although catheter ablation was considered in all patients, it was actually attempted in 20 (74%), either because of insufficient ventricular ectopy (3 patients) or because the patients refused the procedure (4 patients). In the 14 patients in whom clinical ventricular arrhythmia was only induced by isoproterenol infusion, the ablation was guided by both activation and pace mapping. In the remaining 6

Figure 2

Electrocardiographic and Histopathological Findings in a Representative Patient From Group B

(A) Right anterior oblique view of the right ventricular bipolar voltage map showing a low-amplitude (red indicates ⬍0.5 mV) area in the anteroinfundibular region. (B) Endomyocardial biopsy samples showing fibrofatty replacement (Heidenhain trichrome ⫻40). (C) 12-lead electrocardiogram during clinicallysustained ventricular tachycardia 170 beats/min, with a left bundle branch block/inferior axis morphology.

736

Figure 3

Corrado et al. RVOT Tachycardia

JACC Vol. 51, No. 7, 2008 February 19, 2008:731–9

3-Dimensional Electroanatomical Maps of the RV in 2 Representative Patients Undergoing Catheter Ablation of RVOT Tachycardia

(Left) Voltage mapping (left anterior oblique [LAO] 60°) showing preserved bipolar electrograms amplitude throughout the right ventricular (RV) free wall and septum in a patient from group A. Red dots indicate the site of successful radiofrequency ablation in the anteroseptal surface of the right ventricular outflow tract (RVOT). (Right) Voltage mapping (right anterior oblique 30°) showing electroanatomical scar regions in the RVOT in a patient from group B. Targeted ventricular tachycardia was no longer inducible only after completion of serial point ablations completely encircling areas of abnormal voltages.

dynamically well-tolerated VT recurrences and continued to receive antiarrhythmic drug therapy and/or beta-blockers. Correlation of results. Tables 1 to 3 show the comparison between patients with normal (group A) and abnormal (group B) EVM, with respect to a series of clinical, electrophysiological, and follow-up variables. Compared with patients from group A, those from group B significantly more often had a right precordial QRS duration ⱖ110 ms (p ⫽ 0.001) and VT inducibility at programmed ventricular stimulation (p ⫽ 0.001); late potentials on SAECG reached borderline statistical significance (p ⫽ 0.05). The earliest site of endocardial activation during clinical ventricular arrhythmia occurred at the nonseptal (i.e., free wall) RVOT (rather than at the septal RVOT) in 6 of 20 (30%) patients from group A and in 6 of 7 (86%) patients from group B (p ⫽ 0.024). Right precordial QRS duration ⱖ110 ms showed a sensitivity and a specificity in predicting an abnormal EVM of 71% and 95%, respectively; late potential on SAECG of 57% and 85%, respectively; VT inducibility at programmed ventricular stimulation of 71% and 95%, respectively; and nonseptal origin of VT of 86% and 70%, respectively. Demonstration of RV electroanatomical scar showed a statistically significant correlation with histopathological abnormalities at EMB: 6 of 7 patients from group B (86%) showed myocardial atrophy and fibrofatty myocardial replacement consistent with the diagnosis of ARVC/D (Fig. 2), compared with none of the 20 patients from group A (p ⬍ 0.001). An abnormal EVM had 100% sensitivity and 95% specificity to identify patients with a positive EMB. Three patients (55%) from group B received an implantable defibrillator during the follow-up compared with no patients from group A (p ⫽ 0.012).

Discussion The major finding of the present study is that an early/ minor form of ARVC/D may present clinically as RVOT tachycardia in the absence of RV dilation/dysfunction, thus mimicking idiopathic RVOT tachycardia. Electroanatomical voltage mapping is able to identify such concealed ARVC/D variants by detecting RV electroanatomical scars that correlate with the histopathological features pathognomonic of the disease. EVM. Electroanatomical voltage mapping by the CARTO system has been recently demonstrated to reliably identify and characterize low-voltage regions (“electroanatomical scar”) (11–14), which in patients with ARVC/D correspond to areas of myocardial depletion and correlate with the histopathological finding of myocyte loss and fibrofatty replacement at EMB (13). The results of the present study confirm and extend these prior observations by indicating that EVM of the RV is a useful electrophysiological test for distinguishing patients with idiopathic RVOT tachycardia from those with an underlying subtle ARVC/D. The technique provided evidence of electroanatomical RV scar(s) in a subset of patients with RVOT tachycardia, despite a normal RV size and function at echocardiography/ angiography. The majority of patients with an abnormal EVM had electroanatomical scars confined to anteroinfundibular free wall; only 2 patients showed multiregional RV scars also involving remote regions of the so-called “triangle of dysplasia” such as the inferobasal or the apical areas. In our study, the segmental nature of RV lesions with predominant involvement of the free wall of the RVOT may explain why there were no significant changes in overall RV volume

JACC Vol. 51, No. 7, 2008 February 19, 2008:731–9

and ejection fraction. This is in keeping with previous studies showing that some patients with localized ARVC/D, particularly in the infundibulum, may exhibit normal RV volumes and preserved RV ejection fraction at angiography (13). Moreover, it is problematic to detect by current imaging techniques segmental ventricular lesions localized to the RVOT and RV anterior free wall (22,23). A recent angiographic study of computer-based quantitative segmental contraction analysis of the RV free wall demonstrated that wall motion is nonuniform in different RV regions: tricuspid valve zones show the greatest movement during contraction, whereas anterior and infundibular regions the least movement (24). In the present study, we demonstrated that EVM, by assessing the electrical rather than the mechanical effects of loss of RV myocardium, obviated limitations in RVOT wall motion analysis and increased the sensitivity for detecting otherwise concealed ARVC/D myocardial substrate. This is in agreement with previous data on EVM in ARVC/D patients indicating that RV electroanatomical scars may be demonstrated in the absence of detectable wall motion abnormality (13). EMB. Prior studies on EMB in patients with RVOT tachycardia resulted in contradictory findings, most likely because of patient selection bias (2,25,26). In our study, fibrofatty myocardial replacement at EMB was distinctively demonstrated in patients with RV electroanatomical scar. This is in agreement with a previous study in ARVC/D patients showing a strong association between abnormal voltage map and histopathological alterations (13). Demonstration of fibrofatty myocardial replacement on EMB is considered a major criterion for diagnosis of ARVC/D in the European Society of Cardiology/International Society and Federation of Cardiology Task Force guidelines (16). This substantiates the RV EVM findings and supports the conclusion that RVOT tachycardia in this patient subgroup occurred in the context of ARVC/D. Previous studies. Boulos et al. (27) previously compared electroanatomical findings in patients with an ultimate diagnosis of idiopathic RVOT tachycardia with those in patients who had established ARVC/D. They found that mapping results were in concordance with previous clinical diagnosis, by showing normal voltages in the idiopathic RVOT tachycardia group and abnormal low-amplitude areas in ARVC/D patients. However, in this investigation a histologic study to validate the clinical diagnosis was not done. Our study was designed to evaluate the accuracy of EVM to detect an otherwise concealed electroanatomical substrate in a series of patients referred for catheter ablation of RVOT tachycardia, in the absence of RV dilation/ dysfunction. Besides the different study design, discrepancy between the 2 investigations may be explained by different map density. Acquired voltage maps in the present study had a significantly higher density than that obtained in the Boulos et al. (27) study, with average sampled points of 187 ⫾ 16 versus 97 ⫾ 9, respectively.

Corrado et al. RVOT Tachycardia

737

Several previous studies have demonstrated that CMR detects ARVC/D-like structural and wall motion abnormalities in a high proportion of patients with RVOT tachycardia (28 –30). However, the clinical and prognostic significance of such findings is uncertain, because of several limitations and a high degree of interobserver variability in the CMR evaluation of the RV. Particularly, CMR has been implicated in overdiagnosis of ARVC/D based on the finding that free-wall thinning and increased intramyocardial fat as well as global or regional RV dysfunction are also evidenced in healthy subjects (31,32). A recent CMR study focused on RV wall motion pattern in normal subjects reported the presence of wall motion abnormalities in 93.1% of them, including areas of apparent dyskinesia in 75.9% and bulging in 27.6% (33). All these data indicate that conventional CMR may further confuse differential diagnosis between idiopathic RVOT tachycardia and ARVC/D by showing equivocal RV structural and functional abnormalities. Ablation therapy. Previous studies showed the good acute success rate of catheter ablation of RV tachycardia, either idiopathic (1,10,28,29) or associated with ARVC/D (12,14,34,35). However, in patients with ARVC/D, VT recurrences are common (up to 60% of the cases) and may lead to sudden death. The discrepancy between the good acute results and the unfavorable long-term outcome may be explained by the progressive nature of ARVC/D, which predisposes to the occurrence of new and malignant arrhythmogenic substrates over time (34). Accordingly, in our study, the short-term success of catheter ablation did not differ between patients with normal and those with abnormal EVM (85% vs. 89%). However, 3 patients with evidence of RV electroanatomical scar experienced lifethreatening VT during follow-up (despite previously successful catheter ablation in 2 patients) and required implantable cardioverter-defibrillator therapy, compared with none of patients with normal EVM. These findings indicate that the subset of patients with RVOT tachycardia and electroanatomical evidence of RV scar tend toward a worse clinical outcome with an increased risk of sudden arrhythmic death. Potential study limitations. The study population comprised a selected subset of patients with RVOT tachycardia and normal RV/LV function, who underwent further evaluation because of suspicious clinical findings. The prevalence of ARVC/D-related RVOT tachycardia might not be so high in an unselected group of patients with RVOT tachycardia. The unusually high percentage of competitive athletes is explained by the Italian pre-participation evaluation unmasking athletes with ventricular arrhythmias. In patients with ARVC/D, mechanical stress such as that occurring during training and sports competition may exert adverse effects by worsening myocyte death and triggering ventricular arrhythmias (3–5,9).

738

Corrado et al. RVOT Tachycardia

Conclusions Clinical implications. We demonstrated that some patients with RVOT tachycardia in the absence of RV dilation/dysfunction show RVOT electroanatomical scars in association with histopathological features pathognomonic of ARVD/C (i.e., fibrofatty myocardial replacement) and have a malignant arrhythmic course. These findings are consistent with the current perspective on the ARVC/D natural history, with an early “concealed” phase characterized by subtle RV structural changes, which may be confined to 1 region of the so-called triangle of dysplasia, and, nevertheless, predispose to ventricular tachyarrhythmias or sudden death (4,5). This supports the conclusion that our patients from group B had a segmental form of ARVC/D rather than an idiopathic RVOT tachycardia with a nonspecific focal myocardial damage. Clinical predictors of RV electroanatomical scars were QRS prolongation in the leads exploring the RVOT, late potentials, VT inducibility at programmed ventricular stimulation, and VT origin from the nonseptal RVOT. A corollary is that the clinical finding of increased right precordial QRS duration and/or late potentials in patients presenting with RVOT tachycardia should raise the suspicion of a concealed ARVC/D, even in the presence of normal ventricular size and function. Electrophysiological study may be of limited value in the differential diagnosis between idiopathic and ARVC/D-related RVOT tachycardia because a proportion of patients with spontaneous VT are not inducible regardless of the underlying substrate and because idiopathic VT not rarely originates from nonseptal RVOT. Right ventricular EVM, in addition to conventional electrophysiological study, offers the potential to directly identify RVOT electroanatomical scars, which are highly predictive of histopathological fibrofatty myocardial replacement (sensitivity of 100% and specificity of 95%). Accordingly, further investigation by EMB should be reserved to selected cases in which clinical, electrophysiological, and electroanatomical findings are inconclusive and histologic validation of myocardial substrate is necessary to achieve a definitive differential diagnosis. Reprint requests and correspondence: Dr. Domenico Corrado, Department of Cardiac, Thoracic and Vascular Sciences, University of Padua Medical School, Via Giustiniani, 2-35121 Padova, Italy. E-mail: [email protected].

REFERENCES

1. Baxton AE, Waxman HL, Marchlinski FE, Simson MB, Cassidy D, Josephson ME. Right ventricular tachycardia: clinical and electrophysiologic characteristics. Circulation 1983;68:917–27. 2. Lerman BB, Stein K, Engelstein ED, et al. Mechanism of repetitive monomorphic ventricular tachycardia. Circulation 1995;92:421–9. 3. Thiene G, Nava A, Corrado D, Rossi L, Pennelli N. Right ventricular cardiomyopathy and sudden death in young people. N Engl J Med 1988;318:129 –33.

JACC Vol. 51, No. 7, 2008 February 19, 2008:731–9 4. Basso C, Thiene G, Corrado D, Angelini A, Nava A, Valente M. Arrhythmogenic right ventricular cardiomyopathy: dysplasia, dystrophy or myocarditis? Circulation 1996;94:983–91. 5. Corrado D, Basso C, Thiene G, et al. Spectrum of clinicopathologic manifestations of arrhythmogenic right ventricular cardiomyopathy/ dysplasia: a multicenter study. J Am Coll Cardiol 1997;30:1512–20. 6. Pederson DH, Zipes DP, Foster PR, Troup PJ. Ventricular tachycardia and ventricular fibrillation in a young population. Circulation 1979;60:988 –92. 7. Maddox K. Intermittent ventricular tachycardia in youth: report of case with fatal termination. Am Heart J 1947;33:739 – 40. 8. Lesch M, Lewis E, Humphries JO, Ross RS. Paroxysmal ventricular tachycardia in the absence of organic heart disease. Ann Intern Med 1967;66:950 – 60. 9. Corrado D, Thiene G, Nava A, Rossi L, Pennelli N. Sudden death in young competitive athletes: clinicopathologic correlations in 22 cases. Am J Med 1990;89:588 –96. 10. O’Donnell D, Cox D, Bourke J, Mitchell L, Furniss S. Clinical and electrophysiological differences between patients with arrhythmogenic right ventricular dysplasia and right ventricular outflow tract tachycardia. Eur Heart J 2003;24:801–10. 11. Boulos M, Lashevsky I, Reisner S, Gepstein L. Electroanatomical mapping of arrhythmogenic right ventricular dysplasia. J Am Coll Cardiol 2001;38:2020 –7. 12. Marchlinski FE, Zado E, Dixit S, et al. Electroanatomic substrate and outcome of catheter ablative therapy for ventricular tachycardia in setting of right ventricular cardiomyopathy. Circulation 2004;110: 2293– 8. 13. Corrado D, Basso C, Leoni L, et al. Three-dimensional electroanatomic voltage mapping increases accuracy of diagnosing arrhythmogenic right ventricular cardiomyopathy/dysplasia. Circulation 2005; 111:3042–50. 14. Verma A, Kilicaslan F, Schweikert RA, et al. Short- and long-term success of substrate-based mapping and ablation of ventricular tachycardia in arrhythmogenic right ventricular dysplasia. Circulation 2005; 111:3209 –16. 15. Yoerger DM, Marcus F, Sherrill D, et al. Multidisciplinary study of right ventricular dysplasia investigators. Echocardiographic findings in patients meeting task force criteria for arrhythmogenic right ventricular dysplasia: new insights from the multidisciplinary study of right ventricular dysplasia. J Am Coll Cardiol 2005;45:860 –5. 16. McKenna WJ, Thiene G, Nava A, et al. Diagnosis of arrhythmogenic right ventricular dysplasia/cardiomyopathy. Br Heart J 1994;71:215– 8. 17. Klein H, Karp RB, Kouchoukos NT, Zorn GL Jr., James TN, Waldo AL. Intraoperative electrophysiologic mapping of the ventricles during sinus rhythm in patients with a previous myocardial infarction. Identification of the electrophysiologic substrate of ventricular arrhythmia. Circulation 1982;66:847–54. 18. Cassidy DM, Vassallo JA, Miller JM, et al. Endocardial catheter mapping in patients in sinus rhythm: relationship to underlying heart disease and ventricular arrhythmias. Circulation 1986;73:645–52. 19. Marchlinski FE, Callans DJ, Gottlieb CD, Zado E. Linear ablation lesions for control of unmappable ventricular tachycardia in patients with ischemic and nonischemic cardiomyopathy. Circulation 2000; 101:1288 –96. 20. Hsia HH, Callans DJ, Marchlinski FE. Characterization of endocardial electrophysiologic substrate in patients with nonischemic cardiomyopathy and monomorphic ventricular tachycardia. Circulation 2003;108:704 –10. 21. Angelini A, Basso C, Nava A, Thiene G. Endomyocardial biopsy in arrhythmogenic right ventricular cardiomyopathy. Am Heart J 1996; 132:203– 6. 22. Daubert JC, Descaves C, Foulgoc JL, Bourdonnec C, Laurent M, Gouffault J. Critical analysis of cineangiographic criteria for diagnosis of arrhythmogenic right ventricular dysplasia. Am Heart J 1988;115: 448 –54. 23. Scognamiglio R, Fasoli G, Ponchia A, Thiene G, Nava A, Daliento L. Contrast and two-dimensional echocardiography in right ventricular dysplasia: comparison with biopsy. Cardiovasc Imag 1990;2:17–21. 24. Indik JH, Dallas WJ, Ovitt T, Wichter T, Gear K, Marcus FI. Do patients with right ventricular outflow tract ventricular arrhythmias have a normal right ventricular wall motion? A quantitative analysis compared to normal subjects. Cardiology 2005;104:10 –5.

Corrado et al. RVOT Tachycardia

JACC Vol. 51, No. 7, 2008 February 19, 2008:731–9 25. Mehta D, Odawara H, Ward DE, Davies MJ, Camm AJ. Echocardiographic and histologic evaluation of the right ventricle in ventricular tachycardias of left bundle branch morphology without overt cardiac abnormality. Am J Cardiol 1989;63:939 – 44. 26. White RD, Trohman RG, Flamm SD, et al. Right ventricular arrhythmia in the absence of arrhythmogenic dysplasia: MR imaging of myocardial abnormalities. Radiology 1998;207:743–51. 27. Boulos M, Lashevsky I, Gepstein L. Usefulness of electroanatomical mapping to differentiate between right ventricular outflow tract tachycardia and arrhythmogenic right ventricular dysplasia. Am J Cardiol 2005;95:935– 40. 28. Carlson MD, White RD, Trohman RG, et al. Right ventricular outflow tract tachycardia: detection of previously unrecognized anatomic abnormalities using cine magnetic resonance imaging. J Am Coll Cardiol 1994;24:720 –7. 29. Globits S, Kreiner G, Frank H, et al. Significance of morphological abnormalities detected by MRI in patients undergoing successful ablation of right ventricular outflow tract tachycardia. Circulation 1997;96:2633– 40. 30. Markowitz SM, Litvak BL, Ramirez de Arellano EA, Markisz JA, Stein KM, Lerman BB. Adenosine-sensitive ventricular tachycardia:

31. 32. 33.

34.

35.

739

right ventricular abnormalities delineated by magnetic resonance imaging. Circulation 1997;96:1192–200. Bomma C, Rutberg J, Tandri H, et al. Misdiagnosis of arrhythmogenic right ventricular dysplasia/cardiomyopathy. J Cardiovasc Electrophysiol 2004;15:300 – 6. Bluemke DA, Krupinski EA, Ovitt T, et al. Imaging of arrhythmogenic right ventricular cardiomyopathy: morphologic findings and interobserver reliability. Cardiology 2003;99:153– 62. Sievers B, Addo M, Franken U, Trappe HJ. Right ventricular wall motion abnormalities found in healthy subjects by cardiovascular magnetic resonance imaging and characterized with a new segmental model. J Cardiovasc Magn Reson 2004;6: 601– 8. Wichter T, Hindricks G, Kottkamp H, Breithardt G, Borggrefe M. Catheter ablation of ventricular tachycardia. In: Nava A, Rossi L, Thiene G, editors. Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia. Amsterdam, the Netherlands: Elsevier Amsterdam, 1997;376 –91. Ellison KE, Friedman PL, Ganz LI, Stevenson WG. Entrainment mapping and radiofrequency catheter ablation of ventricular tachycardia in right ventricular dysplasia. J Am Coll Cardiol 1998;32: 724 – 8.