Septal ventricular arrhythmias in the presence of structural

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1 Intramural Idiopathic Ventricular Arrhythmias Originating in the Intraventricular Septum Mapping and Ablation Miki Yokokawa, MD; Eric Good, DO; Aman Chugh, MD; Frank Pelosi, Jr, MD; Thomas Crawford, MD; Krit Jongnarangsin, MD; Rakesh Latchamsetty, MD; Hakan Oral, MD; Fred Morady, MD; Frank Bogun, MD Background Intramural septal idiopathic ventricular arrhythmias have not been described systematically. Methods and Results In a consecutive group of 93 patients with idiopathic ventricular arrhythmias referred for ablation, the site of origin of ventricular arrhythmias was assessed by activation mapping and pace-mapping. In 7 of 93 patients (8%), an intramural focus in the interventricular septum was identified. All ventricular arrhythmias arising intramurally had a left bundle-branch block morphology with inferior axis. The intramural focus was effectively ablated from both sides of the septum in 4 patients and from within the septum in 1 patient. The ablation procedure of an intramural focus near the His bundle failed in 2 of 7 patients. ECG and mapping characteristics of the patients with intramural septal ventricular arrhythmias differentiated intramural arrhythmias from other sites of origin. Conclusions Idiopathic septal ventricular arrhythmias can originate from intramural foci. Activation mapping from within a perforator branch within the interventricular septum is helpful in identifying the site of origin of intramural septal arrhythmias. Ablation within the septum or from both sites of the septum may be required to eliminate the targeted arrhythmia. (Circ Arrhythm Electrophysiol. 2012;5: ) Key Words: ventricular arrhythmias ablation intramural focus mapping Septal ventricular arrhythmias in the presence of structural heart disease have been described recently. 1 However, arrhythmias originating from an intramural source in patients without structural heart disease have not been described systematically. They have not been described in recent reviews of ventricular arrhythmias. 2,3 A single recent case report describes the mapping of an intramural arrhythmia that could not be eliminated by ablation. 4 The purpose of this series is to describe the distinguishing features and mapping and ablation of idiopathic arrhythmias originating in the intramural septum. Clinical Perspective on p 263 Methods Patient Characteristics Seven of 93 consecutive patients (8%) referred for ablation of idiopathic ventricular arrhythmias (mean age, years; 52 men; ejection fraction, 52 12%) were found to have a site of origin in the interventricular septum. Five of 7 patients had symptomatic frequent premature ventricular complexes (PVCs) and 2 had frequent asymptomatic PVCs. The left ventricular ejection fraction was reduced in 2 of 7 patients who had ejection fractions of 30% and 42% before the ablation. The mean ejection fraction of the 7 patients was 55 9%. There was no evidence of structural heart disease in these patients, based on echocardiography, stress testing, and cardiac MRI. A 24-hour Holter monitor was performed before ablation and 3 months after ablation. Electrophysiological and ECG characteristics of the 7 patients were compared with 56 patients with idiopathic ventricular arrhythmias that had a left bundle-branch block, inferior-axis morphology. Five of the 93 patients had idiopathic ventricular tachycardia (VT; cycle length, ms), and all 93 patients had frequent PVCs. Electrophysiology Study and Mapping After written informed consent was obtained, a 6F quadripolar electrode catheter was introduced into the right femoral vein and positioned in the right ventricular apex. Three thousand units of heparin were administered. If mapping in the left ventricle or aortic cusps was necessary, the patient received additional heparin to achieve an activated clotting time of 250 to 300 seconds. Programmed right ventricular stimulation was performed using 1 to 4 extrastimuli to assess for inducible VTs. In the presence of frequent spontaneous ectopy, activation mapping was performed using a 3.5-mm-tip catheter (Thermocool Navistar, Biosense Webster, Diamond Bar, CA). Pace-mapping was performed at a pacing cycle length equal to the coupling interval of the spontaneous PVCs. In all patients, a 3-dimensional electroanatomic mapping system was used for activation mapping (Biosense Webster). To identify the site of origin, a multipolar 2.5F catheter (Pathfinder, CARDIMA, Inc, Fremont, CA; Figure 1) was positioned in a Received May 17, 2011; accepted February 8, From the Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI. Correspondence to Frank Bogun, MD, Division of Cardiology, CVC Cardiovascular Medicine, 1500 E Medical Center Dr, SPC 5853, Ann Arbor, MI fbogun@med.umich.edu 2012 American Heart Association, Inc. Circ Arrhythm Electrophysiol is available at DOI: /CIRCEP

2 Yokokawa et al Intramural Focus 259 Figure 1. Left panel, Occlusive venogram of the great cardiac vein in the right anterior oblique position. A multipolar 2.5F catheter is located in a branch of the first septal perforator vein (arrows). Right panel, Coronary angiogram of the left coronary artery indicating that the multipolar catheter (arrows) is adjacent to the first septal perforator branch of the left anterior descending artery. venous septal perforator branch. This was confirmed by venography and coronary angiography (Figure 1). The coronary venous system was always accessed via a right femoral approach by placing a long 8F sheath (SR0 sheath, St Jude Medical, St Paul, MN) into the coronary sinus. The body of the coronary sinus/great cardiac vein as well as the septal branches were then probed with the multielectrode catheter to identify the site of origin. The site of origin was confirmed to be intramural when the catheter located in a septal perforator branch showed the earliest activation time (Figure 2) with a matching pace-map ( 10/12 leads) when pacing was performed at this location (Figure 3). This was accomplished in 2 of 7 patients; in 1 of 7 patients, the catheter was advanced into a perforator branch but the site of origin was not accessible via this perforator branch. In the remaining 4 patients, although septal perforator branches were identified by venography, insertion of the multipolar catheter into these branches was not feasible. Pacing output was set to 10 ma. In the case of a site of origin close to the His bundle, the pacing output was varied to ensure local capture with or without capture of the bundle of His. If a catheter could not be positioned in a perforator branch close to the site of origin of the ventricular arrhythmia (n 5), a septal intramural focus was considered to be present if activation mapping indicated similar timing at the left and right aspect of the septum (Figure 4) and in the presence of a nonmatching pace-map ( 10/12 matching leads) when pacing was performed from the earliest site of endocardial activation at both sides of the septum. Activation maps were performed from within the septum whenever feasible (Figure 5). Radiofrequency Ablation Radiofrequency ablation was performed at the site of earliest activation, if that site was reached with the ablation catheter (Figure 5). If the site was not reached, radiofrequency energy was delivered at both sides of the ventricular septum where the earliest activation times were recorded. Radiofrequency energy was delivered with an irrigated-tip catheter at a power of 15 to 35 W for up to 60 seconds. If the site of origin was near the His bundle, a 6-mm-tip Cryocatheter (Medtronic Inc, Minneapolis, MN) was used for cryoablation, with a target temperature of 80 C and a duration of 4 minutes. Programmed stimulation was repeated after ablation. A 5F conventional ablation catheter (Mariner, Medtronic Inc) was used within the perforator vein (n 1) if the irrigated tip catheter could not be advanced into the perforator branch. Target temperature was set to 55 C with a power up to 50 W. Radiofrequency energy was delivered in unipolar fashion between the catheter tip and a skin electrode. ECG Analysis All 7 patients with an intramural focus had PVCs with a left bundle-branch block, inferior-axis morphology (Figure 6). Fifty-six of the 93 patients also had PVCs or VT with a left bundle-branch block, inferior-axis morphology (control group). The QRS morphology of these ventricular arrhythmias was compared with the morphology of the intramural ventricular arrhythmias. Twenty-six ventricular arrhythmias originated in the right ventricular outflow tract (RVOT), 16 originated in the aortic sinus cusp, 7 originated in the para-hisian region, 3 originated in the pulmonary artery, 2 originated from the epicardium, 1 originated in the left ventricular outflow tract, Figure 2. Surface lead recordings during premature ventricular complex (PVC) in a patient with an intramural PVC focus. Recordings from a multipolar catheter located within a venous septal perforator branch are shown (C1/2 indicates distal electrode pair; C3/4, more proximal electrode pair). The earliest site was recorded by the distal electrode pair C1/2 preceding the onset of the PVC (dotted line) by 26 ms(arrow). Figure 3. Premature ventricular complex (PVC) morphology (left panel) and comparison of the pace-map (right panel) when pacing was performed at the earliest activation site (Figure 2). The pace-map matches with the spontaneous PVC in 10 of 12 leads.

3 260 Circ Arrhythm Electrophysiol April 2012 and 1 originated in the tricuspid annulus. The following ECG parameters were compared: R-wave width, notching of the R-wave in leads V 1 and V 2, interval from beginning of the QRS complex to the nadir of the QRS complex, presence of aqinleads V 1 and V 2, and notching in the down-stroke of the S-wave. The R-wave amplitude was measured from the isoelectric segment preceding the QRS onset; the S-wave was measured from the isoelectric segment preceding the onset of the QRS complex to the nadir of the S-wave. The maximal deflection index was measured (interval measured from the beginning of the QRS complex to the maximum deflection in the precordial leads divided by the QRS duration). 5 ECG data were analyzed by 2 observers blinded to the site of origin of the targeted arrhythmia. Discrepancies were resolved by a third observer. Follow-Up Therapy with antiarrhythmic medications was discontinued if the ablation procedure was acutely successful. Patients were seen in an outpatient clinic 3 and 6 months after the ablation procedure and underwent 24-hour Holter monitoring at 3 months. The median duration of follow-up was 11 5 months. Successful ablation was defined as an 80% decrease in PVC burden at 3 months follow-up. The PVC burden was defined as the percentage of PVCs relative to the total number of QRS complexes on a 24-hour Holter monitor. Figure 4. Activation map of the left and right interventricular septum identifying endocardial break-through sites (orange) of an intramural focus. Right ventricular outflow tract (RVOT), left ventricular outflow tract (LVOT), pulmonary artery (PA) and apex are indicated. Statistical Analysis Continuous variables are expressed as mean 1 SD and were compared with Student t test. Categorical variables were compared with the 2 test. If the sample size was 5 in a given cell, Fisher exact test was used. A probability value 0.05 was considered Figure 5. An ablation catheter (5F) is advanced together with the multipolar mapping catheter (2.5F) into the first septal perforator branch of the great cardiac vein (left panel, right anterior oblique view; right panel, left anterior oblique view). Figure 6. Twelve-lead ECGs of the intramural PVCs.

4 Yokokawa et al Intramural Focus 261 Table 1. Patient Characteristics Variables Intramural (n 7) Control (n 56) P Value Age, y Male sex 5 (71) 28 (50) 0.43 Left ventricular ejection fraction, % Ventricular tachycardia 2/7 3/ PVC burden, % Therapy -blocker 5 (71) 44 (79) 0.65 Calcium channel blocker 2 (29) 12 (21) 0.65 Antiarrhythmic drug 3 (43) 11 (20) 0.18 PVC indicates premature ventricular complex. Values are n (%) or mean 1 SD. statistically significant. The reported probability values were 2-sided. When ECG characteristics of different groups were compared, the Bonferroni correction was used to adjust for multiple comparisons. Results Patient Characteristics In this consecutive series, 7 of 63 patients (11%) with idiopathic, left bundle-branch block, inferior-axis ventricular arrhythmias were found to have a septal, intramural site of origin (Table 1). Two of 7 patients with intramural arrhythmias had previous unsuccessful procedures elsewhere. Two patients with intramural arrhythmias had VT (cycle length, 330 and 385 ms), and the remaining 5 patients had frequent PVCs without inducible VT. Two of 7 patients (29%) with intramural arrhythmias had an abnormal left ventricular ejection fraction compared with 11 of 53 (21%) from the control group (P 1.0). The mean PVC burden before catheter ablation in the intramural PVC group was 24 20%, with a range of 2.1% to 45.7%. The PVCs were monomorphic in 2 patients and pleomorphic in 5 patients. The predominant PVCs were intramural in 1 patient with multiple PVC morphologies. In 5 patients with pleomorphic PVCs, the other sites of origin included the left ventricular outflow tract in 2 patients, the RVOT in 2 patients, and the anterolateral papillary muscle in 1 patient. ECG Characteristics Several ECG characteristics differentiated arrhythmias with intramural septal foci from arrhythmias originating from the RVOT or the para-hisian region (Table 2). However, they could not be distinguished from arrhythmias originating in the aortic cusps. Table 2. ECG Characteristics of Ventricular Arrhythmias Variables Intramural (n 7) Para-Hisian (n 7) Aortic Sinus Cusp (n 16) RVOT (n 26) No. of ventricular arrhythmias Electrogram characteristics QRS width, ms Early transition V 3 10 (91)* 5 (63) 14 (88)* 7 (27) Maximal deflection index Lead V 1 R-wave amplitude, mv * NA * S-wave amplitude, mv R-wave width, ms NA S-wave width, ms 52 14* 45 12* QRS onset S-wave nadir interval, ms * Q-wave 4 (36)* 0 (0) 4 (25) 0 (0) QS-wave 3 (27) 8 (100)* 1 (6) 1 (4) Notching in R-wave 1/8 (13) NA 3/15 (20) 3/25 (12) Notching in S-wave 0/11 (0) 0/8 (0) 0/12 (0) 2/26 (8) Lead V 2 R-wave amplitude, mv * S-wave amplitude, mv * * R-wave width, ms * S-wave width, ms QRS onset S-wave nadir interval, ms * Q-wave 2 (18) 1 (13) 0 (0) 0 (0) QS-wave 0 (0) 0 (0) 0 (0) 0 (0) Notching in R-wave 2 (18) 2 (25) 3 (19) 4 (15) Notching in S-wave 1/10 (10) 2/8 (25) 3/12 (25) 3/26 (12) RVOT indicates right ventricular outflow tract. Values are n (%) or mean 1 SD. *P 0.05 indicated group versus RVOT group, P 0.05 indicated group versus Para-Hisian group. P values reflect multiple comparisons using the Bonferroni correction.

5 262 Circ Arrhythm Electrophysiol April 2012 Table 3. Electrophysiology Characteristics of Ventricular Arrhythmias Variables Intramural (n 7) Control (n 56) P Value No. of ventricular arrhythmias Activation time, ms Endocardium Septum Outflow tract Aortic sinus cusp Within the venous septal NA NA perforator branches Pace-map score at site of earliest activation Endocardium / / Within the venous septal NA NA perforator branches Procedure time, min Fluoroscopy time, min Radiofrequency ablation duration, min Values are n (%) or mean 1 standard deviation. Mapping and Ablation Mapping of the intramural focus was attempted in all patients; in 3 patients, a septal perforator branch was mapped with a multipolar catheter (Tables 3 and 4). In 2 of 3 patients in whom the perforator veins were mapped, the site of origin was reached with the mapping catheter. In the remaining 4 of 7 patients, placement of the mapping catheter into the perforator branches was not accomplished. The mapping data are displayed in Table 4. The origins of the PVCs were located in the basal septum in all patients with an intramural focus. The majority of the targeted PVCs were acutely abolished in 5 of 7 patients. In 1 of these patients, although most of the intramural PVC morphologies were eliminated, 1 morphology was still present at the end of the procedure. In 2 patients, the intramural focus was mapped to the His bundle, where the activation time on the right ventricular endocardium was ms and on the left ventricular endocardium was 32 7 ms. Pace-mapping showed matching QRS complexes in 10 of 12 leads in both patients from Table 4. Activation Time of Patients With Intramural Premature Ventricular Complexes both sides of the septum at the endocardial breakthrough sites. When cryoenergy was applied at both sides of the septum, there was temporary atrioventricular block in 1 patient and temporary PR prolongation in another patient. Atrioventricular conduction resumed and normalized after cryoenergy was discontinued. In the control group, 51 of 56 patients (91%) had a successful ablation outcome. No complications other than the temporary atrioventricular block occurred during the mapping/ablation procedure or during follow-up. Ablation Data For intramural arrhythmias, an average of 17 8 radiofrequency energy applications were delivered with a total radiofrequency energy duration of 16.1 minutes intramurally and minutes endocardially (Table 3). The mean procedure time was minutes, and the mean fluoroscopy time was minutes. Cryoablation was used for ablation in 2 patients with an intramural focus near the His bundle for a total of 14 3 minutes. Follow-Up The mean PVC burden in the 5 patients with intramural PVCs decreased from 24 20% before ablation to 2 3% at 4 3 months after ablation (P 0.03). Total follow-up time was 11 5 months. Five patients from the control group had recurrent persistent palpitations with a PVC burden of 15 3% during follow-up. One patient with pleomorphic PVCs had recurrence of a PVC morphology that was mapped to the anterolateral papillary muscle. The intramural arrhythmia did not recur in this patient. The left ventricular ejection fraction in the 5 patients with intramural ventricular arrhythmias changed from 55 9% to 58 8% (P 0.6). In the 2 patients with decreased ejection fraction before the ablation, the ejection fraction improved from 30% and 42% to 55% and 50%, respectively (both had effective ablation procedures). Discussion Main Findings In this consecutive patient series, 10% of the patients with idiopathic ventricular arrhythmias and a left bundle-branch block, inferior-axis morphology had a septal intramural focus Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 No. of ventricular arrhythmias Activation time, ms Endocardium LV septum RV septum Aortic sinus cusp Within the venous septal NA NA NA NA NA perforator branches Cryoablation No No Yes No Yes No No Location of energy delivery LV/RV endocardium Intramural Para-His LV/RV endocardium Para-His LV/RV endocardium LV/RV endocardium LV indicates left ventricle; RV, right ventricle. Values are n (%) or mean 1 SD.

6 Yokokawa et al Intramural Focus 263 that required either ablation within the septum or at both sides of the septum. Intramural septal ventricular arrhythmias can be mapped and ablated endocardially or intramurally. Identification and Ablation of the Site of Origin To eliminate an intramural idiopathic ventricular arrhythmia, the site of origin must be identified. The ideal way to reach the site of origin of a septal intramural focus is to advance a flexible multipolar catheter within one of the perforator veins. This was achieved in 2 of 7 patients with an intramural focus. An alternative approach is to assess the endocardial breakthrough sites on both sites of the septum. Despite the focus being intramural, an effective ablation was achieved in 5 of 7 patients. In both patients with an unsuccessful outcome, the arrhythmia focus was close to the His bundle, and a cryoablation catheter was used. This resulted in a temporary atrioventricular block in one of the patients and temporary PR prolongation in the other patient. It is possible that the arrhythmia focus might have been eliminated, if radiofrequency energy had been used, but this probably would have resulted in permanent AV block. ECG Features There are several ECG features including R-wave and S-wave characteristics in V 1 /V 2 that we did not observe in a control group of patients with idiopathic ventricular arrhythmias originating from the RVOT or the para-hisian region. However these features are not specific to intramural arrhythmias and also were observed in ventricular arrhythmias originating in an aortic cusp. None of the analyzed ECG characteristics differentiated intramural arrhythmias from arrhythmias originating in the aortic cusps. Prior Studies In recent reports about idiopathic VTs, an intramural origin is not mentioned. 2,3 It is possible that unawareness of this origin may have resulted in unsuccessful ablation procedures. The prevalence of intramural septal foci in this consecutive series is relatively high, but it matches with reports were the failure rates of idiopathic ventricular arrhythmias ranges between 15% to 21%. 6 8 A large number of arrhythmias with ineffective ablations were mapped to the interventricular septum, 6,7,9 suggesting that an intramural septal focus might have been present. Clinical Implications Failure to ablate a left bundle-branch block, inferior-axis morphology ventricular arrhythmia in a patient without structural heart disease may be due to an intramural septal focus. The absence of a matching pace-map at the site of earliest endocardial ventricular activation as well as distinct ECG features indicates an intramural septal focus. The site of origin can be confirmed by positioning a mapping catheter in a venous septal perforator branch of the great cardiac vein. Effective ablation from within this vein or from both sides of the endocardial breakthrough is possible. Acknowledgments Drs Bogun and Oral received a grant from the Leducq Foundation. None. Disclosures References 1. Haqqani HM, Tschabrunn CM, Tzou WS, Dixit S, Cooper JM, Riley MP, Lin D, Hutchinson MD, Garcia FC, Bala R, Verdino RJ, Callans DJ, Gerstenfeld EP, Zado ES, Marchlinski FE. Isolated septal substrate for ventricular tachycardia in nonischemic dilated cardiomyopathy: incidence, characterization, and implications. Heart Rhythm. 2011;8: Stevenson WG, Soejima K. Catheter ablation for ventricular tachycardia. Circulation. 2007;115: Aliot EM, Stevenson WG, Almendral-Garrote JM, Bogun F, Calkins CH, Delacretaz E, Della Bella P, Hindricks G, Jais P, Josephson ME, Kautzner J, Kay GN, Kuck KH, Lerman BB, Marchlinski F, Reddy V, Schalij MJ, Schilling R, Soejima K, Wilber D. EHRA/HRS expert consensus on catheter ablation of ventricular arrhythmias: developed in a partnership with the European Heart Rhythm Association (EHRA), a registered branch of the European Society of Cardiology (ESC), and the Heart Rhythm Society (HRS); in collaboration with the American College of Cardiology (ACC) and the American Heart Association (AHA). Heart Rhythm. 2009; 6: Yamada T, Okada T, Murakami Y, Yoshida N, Murohara T, Kay GN. Premature ventricular contractions arising from the intramural ventricular septum. Pacing Clin Electrophysiol. 2009;32:e1 e3. 5. Daniels DV, Lu YY, Morton JB, Santucci PA, Akar JG, Green A, Wilber DJ. Idiopathic epicardial left ventricular tachycardia originating remote from the sinus of Valsalva: electrophysiological characteristics, catheter ablation, and identification from the 12-lead electrocardiogram. Circulation. 2006;113: Rodriguez LM, Smeets JL, Timmermans C, Wellens HJ. Predictors for successful ablation of right- and left-sided idiopathic ventricular tachycardia. Am J Cardiol. 1997;79: Tada H, Tadokoro K, Ito S, Naito S, Hashimoto T, Kaseno K, Miyaji K, Sugiyasu A, Tsuchiya T, Kutsumi Y, Nogami A, Oshima S, Taniguchi K. Idiopathic ventricular arrhythmias originating from the tricuspid annulus: prevalence, electrocardiographic characteristics, and results of radiofrequency catheter ablation. Heart Rhythm. 2007;4: Vestal M, Wen MS, Yeh SJ, Wang CC, Lin FC, Wu D. Electrocardiographic predictors of failure and recurrence in patients with idiopathic right ventricular outflow tract tachycardia and ectopy who underwent radiofrequency catheter ablation. J Electrocardiol. 2003;36: Tada H, Ito S, Naito S, Kurosaki K, Kubota S, Sugiyasu A, Tsuchiya T, Miyaji K, Yamada M, Kutsumi Y, Oshima S, Nogami A, Taniguchi K. Idiopathic ventricular arrhythmia arising from the mitral annulus: a distinct subgroup of idiopathic ventricular arrhythmias. J Am Coll Cardiol. 2005;45: CLINICAL PERSPECTIVE Identification and management of idiopathic intramural ventricular arrhythmias (VA) can be challenging. In a consecutive group of 93 patients, we describe 7 patients (8%) with idiopathic, intramural VAs from the interventricular septum. All VAs had a left bundle-branch block inferior axis morphology. The analyzed ECG features were not specific enough to differentiate intramural VA from VA originating from the aortic cusps. The intramural focus could be ablated in 5 of 7 patients via an endocardial approach from the left and right interventricular septum or from within the myocardium via a perforator vein. Knowledge of this type of arrhythmia will help to further improve treatment of patients with idiopathic VAs.