Catheter Ablation of Idiopathic Premature Ventricular Contractions and Ventricular Tachycardias Originating from Right Ventricular Septum

Background Idiopathic premature ventricular contractions (PVCs) and ventricular tachycardias (IVTs) originating from the subtricuspid septum and near the His bundle have been reported. However, little is known about the prevalence, distribution, electrocardiographic characteristics and the efficacy of radiofrequency catheter ablation (RFCA) for the ventricular arrhythmias arising from the right ventricular (RV) septum. This study aimed to investigate electrocardiographic characteristics and effects of RFCA for patients with symptomatic PVCs/IVTs, originating from the different portions of the RV septum. Methodology/Principal Findings Characteristics of body surface electrocardiogram and electrophysiologic recordings were analyzed in 29 patients with symptomatic PVCs/IVTs originating from the RV septum. Among 581 patients with PVCs/IVTs, the incidence of ventricular arrhythmias originating from the RV septum was 5%. Twenty (69%) had PVCs/IVTs from the septal portion of the tricuspid valvular RV region (3 from superoseptum, 15 from midseptum, 2 from inferoseptum), and 9 (31%) from the septal portion of the basal RV (1 from superoseptum, 4 from midseptum, 4 from inferoseptum). There were different characteristics of ECG of PVCs/VT originating from the different portions of the RV septum. Twenty-seven of 29 patients with PVCs/IVTs arising from the RV septum were successfully ablated (93.1% acute success). Conclusions/Significance ECG characteristics of PVCs/VTs originating from the different portions of the RV septum are different, and can help regionalize the origin of these arrhythmias. The septal portion of the tricuspid valvular RV region was the preferential site of origin. RFCA was effective and safe for the PVCs/IVTs arising from the RV septum.


Introduction
The majority of idiopathic right ventricular arrhythmias (VAs), including idiopathic premature ventricular contractions (PVCs) and ventricular tachycardias (IVTs), originate from the right ventricular outflow tract (RVOT), with a small part of them originating from the inflow, free wall, or apex of the right ventricle [1][2][3][4][5][6]. Idiopathic PVCs and VTs originating from the right ventricular (RV) septum are rare. Only few cases of idiopathic VAs have been reported to originate from the subtricuspid septum and near the His bundle [7][8][9][10]. However, little is known about the prevalence, distribution, electrocardiographic (ECG) characteristics and the efficacy of radiofrequency catheter ablation (RFCA) for the VAs arising from the RV septum. The purpose of this study was to analyze the ECG characteristics and the outcome of catheter ablation for such PVCs/IVTs originating from the RV septum.

Study Population
From July 2006 to January 2012, a total of 581 patients (250 men and 331 women; age 46.9617.2 years [mean6SD] ) without structural heart disease were presented for catheter ablation for PVCs/IVTs in our hospital. Twenty-nine of the 581 patients were found to have idiopathic PVCs/IVTs originating from the RV septum and are the focus of the present study. All patients were verified as having no structural heart disease, including coronary artery disease, valvular heart disease, congenital heart disease, left ventricle hypertrophy, and right ventricle abnormalities by routine biochemistry tests, X-ray, color echocardiography examination, exercise electrocardiogram testing, magnetic resonance imaging (MRI), and/or cardiac catheterization with coronary angiography or RV contrast angiography. Before RFCA, a 12-lead ECG was obtained, and 24 h of ambulatory ECG monitoring (Holter) was carried out at least once. The ECG was monitored for 24 h just before catheter ablation. The 29 patients with idiopathic PVCs/ IVTs from the RV septum were compared with a randomly chosen series of 125 patients with idiopathic PVCs/IVTs in whom the site of origin was in the RVOT (n = 87, 56 women and 31 men; age 48.1617.2 years) or the RV free wall (n = 38, 13 women and 25 men; age 36.2617.7 years). A pace mapping study was also performed in 10 control subjects (6 women and 4 men; age 37.6615.1 years) without structural heart disease after successful ablation of their original atrioventricular nodal reentrant tachycardia to determine the ECG characteristics of idiopathic PVCs/ IVTs originating from the RV septum.

Ethics Approval
Ethical approval was obtained from the Ethics Committee of the Second Affiliated Hospital of Wenzhou Medical College, and All participants consented to the experimental procedures. Written informed consent was obtained from each participant.

Inclusion Criteria
The selection criteria of patients were the following reasons : (1) frequent or consecutive PVC occurrence, the average PVC count $10000/24 h; (2) inability of the patient to tolerate PVCs/IVTs or unsuccessful treatment with at least one antiarrhythmic drug; (3) no structural heart disease; and (4) consent for the catheter ablation procedure.

Electrophysiologic Study and RFCA
Anti-arrhythmic drugs were withdrawn in all patients at least five half-lives before ablation, with the exception of amiodarone that was withdrawn eight weeks before intervention. Standard multielectrode catheters were inserted and positioned in the RV apex, RVOT, and His-bundle region through femoral veins under fluoroscopic guidance. A programmed electrical stimulation was performed from the RV apex and RVOT at basic drive cycle lengths of 600, 500, and 430 ms, delivering a maximum of three extrastimuli. If the clinical arrhythmia did not occur spontaneously and was not induced at baseline, intravenous isoproterenol (2-4 mg/min) was administered to induce arrhythmia. A 12-lead surface ECG was monitored and recorded on a multichannel oscilloscopic recorder. Detailed endocardial activation mapping and pace mapping were performed using an 8F quadripolar catheter with a deflectable tip and a 4-mm distal electrode. If the ventricular electrograms from the RV septum were the earliest of the entire RV endocardial mapping sites, we occasionally mapped the aortic valve cusps.  The target site for RFCA was determined by activation mapping (earliest local activation time preceding the earliest surface QRS by $20 msec) in patients with frequent PVCs/ sustained IVT, and by pace mapping ($11/12-lead concordance of major and minor deflections between the pace map and the clinical PVCs) in those with infrequent arrhythmia. After the target site was located, RFCA was applied in all patients by using irrigated-tip catheter (43uC, 30 W, 20 ml/min) with the three-dimensional mapping (Ensite NavX system or Carto XP or Carto 3 system) or a conventional catheter under temperature control (target temperature 55uC, and starting power of 20 W with gradual titration to a maximum power of 50 W). If the PVCs/ IVTs terminated within 10 s of ablation, or if they increased in frequency within the initial 10 s of ablation, additional current was applied for another 60 to 180 s. If PVCs/IVTs did not terminate within 10 s, the radiofrequency energy application was terminated and another target site was sought. Acute procedural successful ablation was defined as complete elimination of spontaneous or inducible VAs. Programmed electrical stimulation was repeated at 30 min after the last application of radiofrequency energy to confirm the absence of inducible VAs before removing all catheters and sheaths. If the site demonstrating a perfect pace map was exactly where the largest His bundle potential was recorded, RF ablation could not be applied in order to avoid atrioventricular nodal block. If the best pace mapping site was close to the His bundle, the RF energy was cautiously delivered starting with a low power setting at the site that was at least 5 mm away from the recording site of the largest His bundle potential.

Definition of PVCs/IVTs Originating from the RV Septum
To facilitate the identification of region-specific ECG features that might suggest an RV septum origin, sites of origin of PVCs/ IVTs in the RV septum from top to bottom of the RV septum were grouped into distinct anatomic segments: superoseptum (from top to the His bundle), midseptum (from the His bundle to coronary sinus), and inferoseptum (from the coronary sinus to bottom) ( Figure 1). The His bundle region was determined as the site recording the largest His bundle potential. The RV septum was further divided into three regions: a valvular region extending from the tricuspid valve to 2 cm anterior of the valve, and two equal portions between this region and the RV apex (basal and apical region), as previously reported [5,11]. Therefore, we defined 9 distinct anatomic segments ( Figure 1A). We localized the origin

ECG Measurements
Twelve-lead electrocardiograms recorded at a paper speed of 25 mm/s were available for all patients with PVCs/IVTs originating from the RV septum. The analysis of the ECG pattern was focusing on the following characteristics: (1) The QRS morphology of the PVCs/IVTs in all 12 leads, (2) the duration of the QRS complex, (3) the site of R-wave transition in the precordial leads (The transition zone is where the QRS complex changes from predominately negative to predominately positive and the R/S ratio becomes .1), (4) the QS pattern in the precordial leads, (5) the axis deviation. Normal QRS axis is from around 230 to +90 degrees. More negative than 230 degrees is called left axis deviation. More positive than +90 degrees is called right axis deviation.

Pace Mapping Study
The pace mapping study was performed in the 10 control subjects. A 7-F quadripolar catheter was used. A single electrical stimulus was delivered during the end diastole in a bipolar fashion at an output just greater than the diastolic threshold from the distal electrode pair (with the distal electrode as the cathode). The catheter sites were confirmed by multi-plane fluoroscopy, and pacing was performed at these segments of the RV septum in each patient ( Figure 1A). The pacing protocol was performed after a written informed consent was obtained.

Follow-Up
After RFCA, all patients underwent a 48-hour ECG monitoring. Holter was carried out 1 week after RFCA. Patients were not given any antiarrhythmic drugs after RFCA, and underwent Doppler color echocardiography and Holter examination 3 and 6 months after RFCA. ECG, echocardiography and 24-hour ECG monitoring were performed whenever the patient had symptoms suggestive of recurrence of VAs.

Statistical Analysis
All values were expressed as mean value 6 standard deviation (SD). The continuous variables were compared with a Student's ttest for two groups and with analysis of variance (ANOVA) for .2 groups. The categorical data were compared with a Fisher's exact test. The sensitivity, specificity, and positive and negative predictive accuracies of the ECG characteristics to localize the site of origin of PVCs/IVTs were calculated. All tests were 2tailed, and a value of P,0.05 was considered statistically significant.

Study Population
Among patients with PVCs/IVTs, the incidence of VAs originating from the RV septum was 5% (total 29 patients, 18 men and 11 women; mean age 50.3621.3 years (range 8-80 years). The clinical characteristics of the 29 patients included in the study are shown in Table 1. The past medical history was significant for hypertension in eight patients, diabetes in four patients. Symptoms consisted of palpitations (100%), presyncope (3.4%), syncope (3.4%), and chest pain (17.2%). The median duration of symptoms prior to the ablation procedure was 26.5 months (range 4-144). All patients in this study had failed prior antiarrhythmic therapy with 1.660.6 drugs, including amiodarone  Table 1). The PVCs were monomorphic in all patients.

Electrophysiologic Findings and Effect of RFCA
PVCs/IVTs arise from the RV septum in 29 patients, including 20 (69%) from the septal portion of the tricuspid valvular RV region (3 from right superoseptum, 15 from right midseptum, 2 from right inferoseptum), and 9 (31%) from the septal portion of the basal RV (1 from right superoseptum, 4 from right midseptum, 4 from right inferoseptum). No PVCs/IVTs originated from the septal portion of the apical RV. Figure 1B and Table 2 list the detailed VA origin from the RV septum. The PVCs/IVTs occurred spontaneously in 26 patients and was induced by bolus injection of isoproterenol (2 mg) in 3 patients during the electrophysiologic study. Twenty-two of 29 patients underwent the electrophysiologic study using Ensite NavX system or Carto XP system or Carto 3 system, and the remaining 7 patients using conventional mapping techniques. The local ventricular activation time recorded at successful ablation target sites that preceded the onset of the QRS complex was 30.465.4 ms ( Table 2). Successful RFCA in 27 patients could be achieved (93.1% acute procedural success). RFCA could not be applied in the remaining 2 patients because the best pace mapping site was close to the His bundle ( Figure 2). No complications occurred during the mapping or ablation procedure. An average of 3.261.4 (range 2-7) radiofrequency energy applications were delivered with a mean total radiofrequency energy duration of 270.9698.4 (range 62-516)s. The mean fluoroscopy time was 8.062.3 (range 1.8-11.4) min. Patients have been followed-up for 11.268.2 (range 3-36) months. One patient had recurrent VAs after an initially effective procedure. The transthoracic echocardiography demonstrated a decreased LVEDd 6 months after effective RFCA in the patient whose LVEDd was increased prior to ablation (Patient No. 21 in Table 1). No right ventricular dilation, wall motion abnormalities, or ECG abnormalities (i.e., inverted T waves in the right precordial leads, epsilon wave) were found in any of these patients during follow-up. No patient died during follow-up.

ECG Characteristics
General characteristics. All PVCs/IVTs arising from the RV septum had an rS or QS pattern in lead V1 and displayed a left bundle branch block morphology (Figures 2-7 and Table 3). All PVCs/IVTs showed a monophasic R pattern in lead I, 86.2% (25/29) PVCs/IVTs had a QS or qs pattern in lead aVR, and 79.3% (23/29) PVCs/IVTs had a monophasic R pattern in lead aVL. The duration of the QRS complex of the PVCs/IVTs was132610 (range 110-150) ms. The precordial R-wave transition occurred in or earlier than lead V3 in 14 patients, and later than lead V3 in 15 patients (earlier than lead V2 in 2 patients, between lead V2 and V3 in 6 patients, in lead V3 in 6 patients, between lead V3 and V4 in 6 patients, between lead V4 and V5 in 4 patients, between lead V5 and V6 in 2 patients, in lead V6 in 1 patient, later than lead V6 in 2 patients).
Comparison between PVCs/IVTs arising from the tricuspid valvular and basal RV septum. There was no significant difference in QRS duration between the PVCs/IVTs arising from the tricuspid valvular and basal RV septum. The precordial R-wave transition occurred in lead V4 or earlier (!V4) in all of the PVCs/IVTs arising from the tricuspid valvular RV septum, and all patients with the PVCs/IVTs arising from the basal RV septum had a later precordial R-wave transition (.V4) (Figure 8 and Table 4). The earlier precordial R-wave transition (!V4) has a sensitivity of 100%, a specificity of 100%, a negative predictive value of 100%, and a positive predictive value 100% to predict the tricuspid valvular RV septal origin of PVCs/IVTs (Table 5).
Comparison between PVCs/IVTs arising from the RV superoseptum and mid-inferoseptum. PVCs/IVTs arise from the RV septum in 29 patients, including 4 (13.8%) from the RV superoseptum and 25 (86.2%) from the RV midinferoseptum. There was no significant difference in QRS complex duration between the PVCs/IVTs arising from the RV superoseptum and mid-inferoseptum. A QS pattern in lead V1 was observed in 96% (24/25) of the PVCs/IVTs arising from the RV mid-inferoseptum, and an rS pattern in lead V1 was observed in all of PVCs/IVTs arising from the RV superoseptum ( Figure 8 and Table 4). The QS pattern in lead V1 has a sensitivity of 96%, a specificity of 100%, a positive predictive value 100%, and a negative predictive value of 80% to predict the RV midinferoseptal origin of PVCs/IVTs (Table 5). When the origin of the PVCs/IVTs shifted from inferoseptum to midseptum to superoseptum of the RV (Figure 3): R wave amplitude increased and S wave amplitude decreased in leads II, III, aVF and V2-V6; R wave amplitude decreased in lead aVL; QS amplitude increased in lead aVR.
Comparison among PVCs/IVTs arising from the RV septum, RV free wall and RV outflow tract (RVOT). The QRS duration in PVCs/IVTs arising from the RV septum were significantly shorter compared with the arrhythmias arising from the RV free wall (132610 ms VS 159612 ms, P,0.001 ) and RVOT (132610 ms VS 142614 ms, P,0.001) ( Table 6). Right axis deviation was noted in 87.4% (76/87) PVCs/IVTs in the RVOT group, and left axis deviation was noted in 79.3% (23/29) PVCs/IVTs in the RV septum group and in 71.1% (27/38) PVCs/IVTs in the RV free wall group. QS pattern and rS pattern in lead V1 were observed in 82.8% (24/29) and 17.2% (5/29) of the PVCs/IVTs arising from the RV septum, versus 2.3% (2/87) and 97.7% (85/87) of the PVCs/IVTs arising from the RVOT (P,0.001 for both) and 5.3% (2/38) and 94.7% (36/38) of PVCs/ IVTs arising from the RV free wall (P,0.001 for both) (Figure 9 and Table 6). In the RVOT group, 86/87 (98.9%) had a monophasic R pattern in all three inferior leads (II, III, aVF) ( Figure 9 and Table 6). Only 1/29 (3.5%) in the RV septum group and 2/38 (5.3%) in the RV free wall group had a monophasic R pattern in all inferior leads (98.9% VS 3.5%, 98.9% VS 5.3%; both P,0.001) ( Figure 9 and Table 6). The monophasic R pattern in all inferior leads has a sensitivity of 98.9%, a specificity of 95.5%, a positive predictive value 96.6%, and a negative predictive value of 100.00% to predict the RVOT origin of PVCs/IVTs ( Table 7). The QS pattern in lead V1 has a sensitivity of 82.8%, a specificity of 94.7%, a positive predictive value 92.3%, and a negative predictive value of 87.8%, and the QRS duration of !143.5 ms has a sensitivity of 89.7%, a specificity of 89.5%, a positive predictive value 86.7%, a negative predictive value of 91.9%and to predict the RV septum origin of PVCs/IVTs ( Figure 10 and Table 7).

Pace Mapping Study
Because it was difficult to position the catheter in the superoseptal portion of the apical RV region, pace mapping at the region was not performed. The pace mapping was performed at the other 8 segments of the RV septum. The characteristics of the QRS morphology during pacing from the RV septum in 10 subjects were almost identical with those of the PVCs/IVTs arising from the RV septum ( Figure 11). There existed some distinctive ECG characteristics during pacing in 10 subjects ( Figure 11): 1) During pacing from superoseptum to inferoseptum of RV and from tricuspid valvular RV septum to apical RV  Table 4. Comparison of ECG characteristics between PVCs/VTs arising from the tricuspid valvular and basal right ventricular septum, between PVCs/IVTs arising from the RV superoseptum and mid-inferoseptum. septum, R wave amplitude was more lessening and S wave amplitude was more increasing in leads II, III, aVF and V4-V6. 2) During pacing from superoseptum to inferoseptum of RV, R wave amplitude was more increasing and Q wave amplitude was more lessening in lead aVL. 3) A rS pattern in lead V1 was observed only when pacing at the superoseptal portion of the tricuspid valvular RV region, and a QS pattern in lead V1 was always recorded when pacing at the other sites of the RV septum. During pacing from tricuspid valvular RV septum to apical RV septum, the number of precordial leads displaying the QS pattern was more increasing, and the number of precordial leads displaying the R or RS pattern was more decreasing (Figure 11).

Main Findings
The study demonstrated for the first time that 5% of PVCs/ IVTs had an origin at the RV septum, and that the septal portion of the tricuspid valvular RV region was the preferential site of origin, but the site of origin also could be located at the septal portion of the basal RV region. We note different ECG characteristics of PVCs/IVTs originating from the different portions of the RV septum which were confirmed by the pace mapping study and demonstrate that RFCA can be performed safely with good long-term success in preventing symptomatic VAs.

Site-specific ECG Characteristics and their Proposed Mechanisms
Prior studies described VAs originating from the tricuspid annulus and RV septum near the His-bundle in patients without structural heart disease [7][8][9][10]. We and other investigators have recently demonstrated that QRS duration, R-wave transition in the precordial leads, QS pattern in lead V1, and polarity of the QRS complex in the inferior leads were useful to distinguish between PVCs/IVTs originating from the septal portion and free wall of tricuspid annulus [8,9]. A monophasic tall R pattern in lead I, low R wave in leads II and aVF, particularly lower R wave in lead III than in lead II, R wave in lead aVL, relatively narrow QRS duration, QS pattern in lead V1, and tall R wave in V5 and V6 suggest the PVCs/IVTs origin from the RV septum near the His-bundle [10]. Although several studies have reported the PVCs/IVTs arising from the tricuspid annulus and RV septum near the His-bundle, none have systemically determined the prevalence and ECG characteristics of PVCs/IVTs arising from the different sites of the RV septum, based on as many patients as in this study. In the present study, the relatively early precordial R wave transition by lead V4 help us to differentiate the tricuspid valvular septum from the basal RV septal site of origin. Because the origin of VAs in the tricuspid valvular septum was located in the more posterior portion of the RV than that in the basal septum of the RV, more distant from the precordial electrodes, the myocardium near the focus was depolarized in a direction more toward these electrodes. This could account for the earlier precordial R-wave transition (!V4) in the PVCs/IVTs arising from the tricuspid valvular septum than the basal RV septum. In the present study, another interesting finding was that when the origin of the PVCs/IVTs shifted from inferoseptum to midseptum Table 5. The sensitivity, specificity, negative predictive value (NPV) and positive predictive value (PPV) to identify the precise origin of PVCs/IVTs from the right ventricular (RV) septum.  to superoseptum of the RV, R wave amplitude increased and S wave amplitude decreased in leads II, III, aVF and V2-V6, R wave amplitude decreased in lead aVL, and QS amplitude increased in lead aVR. Because the origin of the PVCs/IVTs arising from the RV inferoseptum was located on the right inferior side of the heart, the myocardium would be depolarized in a direction toward the anode of leads aVL, away from the inferior leads, which might account for the findings: lower R wave and greater S wave amplitude in the inferior leads, and greater R wave amplitude in the lead aVL; the origin of the PVCs/IVTs arising from the RV superoseptum was located on the right superior side of the heart, the myocardium would be depolarized in a direction toward the inferior leads, away from the lead aVR and aVL, which might account for the findings: greater R wave and smaller S wave amplitude in the inferior leads, greater QS amplitude in lead aVR, smaller R amplitude in lead aVL. In the present study, the QS pattern in lead V1 and QRS duration were found to be useful to distinguish PVCs/IVTs origin in the RV septum or the RV free wall. Because the magnitude of the initial ventricular force is expected to be much greater in the left ventricle than in the RV, the mean initial QRS vector would be directed to the left posterior and away from the electrode of lead V1 on the horizontal plane, which might predominantly result in a QS pattern in PVCs/IVTs arising from the RV septum. When the VAs focus is located at the RV septum, both ventricles would be activated almost simultaneously, which might result in a shorter QRS duration. In the present study, s or S wave in the inferior leads, particularly in lead III was observed more often PVCs/IVTs arising from the RV septum than that arising from the RVOT. In contrast, the monophasic R pattern in all of the inferior leads was observed more often PVCs/IVTs arising from the RVOT than that arising from the RV septum. Because the RV septum is positioned to the right and inferior to the RVOT. Therefore, in PVCs/IVTs arising from the RV septum, it would be directed more to the left and superiorly than in PVCs/IVTs arising from the RVOT, which may account for the rarities of a monophasic R pattern in all of the inferior leads in PVCs/IVTs arising from the RV septum.

Radiofrequency Ablation
Previous studies have shown that PVCs/IVTs originating from the septal portion of tricuspid annulus and RV septum near the His-bundle can be successfully ablated [7][8][9][10]. In the present  study, we demonstrated that RFCA was effective for eliminating PVCs/IVTs arising from the RV septum. Twenty-seven of 29 patients with PVCs/IVTs arising from the RV septum were successfully ablated (93.1% acute success). In the remaining 2 patients no attempt at ablation was undertaken because the origin of the PVCs/IVTs was found to be parahisian. One patient had recurrent ventricular arrhythmia after successful RFCA during a mean follow-up period of 11.2 months. No significant complications were observed in our patient group confirming the safety of the procedure. Although clinical application of RF energy in the RV septum has proven relatively safe, much care must be taken to avoid the complications, such as atrioventricular node conduction block.

Study Limitations
No abnormalities suggestive of arrhythmogenic right ventricular cardiomyopathy were found by ECG and echocardiography and MRI and right ventricular contrast angiography in any of the patients with the RV septal VAs in the present study. No ECG and echocardiography changes suggestive of arrhythmogenic right ventricular cardiomyopathy were seen during follow up. However, a signal-averaged ECG or endomyocardial biopsy was no performed. Therefore, we could not have completely excluded the possibility of a concealed form of arrhythmogenic right ventricular cardiomyopathy. However, we believe the data presented strongly suggests that the arrhythmias described were truly idiopathic. To increase the accuracy of our study, our results need to be confirmed in additional long-term follow-up. Table 7. The sensitivity, specificity, negative predictive value (NPV) and positive predictive value (PPV) to identify the precise origin of PVCs/IVTs arising from the right ventricular outflow tract (RVOT) and not arising from the RVOT (NRVOT) and PVCs/VTs arising from the RV septum and free wall.