Introduction. CLINICAL RESEARCH Electrophysiology and ablation

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1 Europace (2014) 16, doi: /europace/eut253 CLINICAL RESEARCH Electrophysiology and ablation Electrophysiological and anatomical differences of the slow pathway between the fast slow form and slow slow form of atrioventricular nodal reentrant tachycardia Yosuke Nakatani 1, Koichi Mizumaki 1 *, Kunihiro Nishida 1, Tamotsu Sakamoto 1, Yoshiaki Yamaguchi 1, Naoya Kataoka 1,MasaoSakabe 2, Akira Fujiki 2, and Hiroshi Inoue 1 1 Second Department of Internal Medicine, Graduate School of Medicine, University of Toyama, 2630 Sugitani, Toyama , Japan; and 2 Division of Cardiology, Shizuoka Red Cross Hospital, Shizuoka , Japan Received 9 April 2013; accepted after revision 19 July 2013; online publish-ahead-of-print 20 August 2013 Aims This study aimed to clarify whether electrophysiological and anatomical properties of the slow pathway (SP) could be different between the fast slow form (F/S) and the slow slow form (S/S) atrioventricular nodal reentrant tachycardia (AVNRT).... Methods Nine patients with F/S and 15 patients with S/S of atypical AVNRT were studied. The patients with S/S were divided into and results two groups; those with the anterograde SP being eliminated (S/S asp-e) or preserved (S/S asp-p) during catheter ablation. HA (CS-His) was determined as the difference of the shortest HA interval between the His bundle region and the coronary sinus (CS) region. The ratio of the amplitudes of atrial and ventricular potential (A/V ratio) of the successful ablation site of the SP was also evaluated. Effective refractory period of the retrograde SP was shorter and HA intervals during both tachycardia and ventricular pacingwerelonger in F/S than in S/S. HA (CS-His) did not differ between F/S and S/ S( vs ms, NS). The A/V ratio was significantly greater in the S/S asp-p group compared with the both groups of F/S and S/S asp-e ( vs and ms, P, 0.01).... Conclusion Properties of the retrograde SP differ between F/S and S/S of AVNRT. Fast slow form may utilize the same pathway for the retrograde conduction as the anterograde SP in S/S Keywords Atrioventricular nodal reentrant tachycardia Electrophysiology Catheter ablation Slow pathway Intermediate pathway Reentrant circuit Introduction Atrioventricular nodal reentrant tachycardia (AVNRT) has three subforms, namely, the slow fast form (S/F), fast slow form (F/S), and slow slow form (S/S) the latter two forms are called atypical AVNRT. 1,2 Each subform utilizes different atrioventricular (AV) nodal pathways for the reentrant circuit. Fast slow form utilizes a fast pathway (FP) for the anterograde limb and a slow pathway (SP) for the retrograde limb of the reentrant circuit, and S/S utilizes two distinct SPs for anterograde and retrograde limbs of the reentrant circuit. Therefore, both of the two forms of atypical AVNRT utilize the SP for the reentrant circuit; however, anatomical location of these SPs has not been fully elucidated. Yamabe et al. 3,4 confirmed using the single extrastimulation method that the location of the reentrant circuit was different between the two subforms. Ooie et al. 5 investigated the location of the anterograde and retrograde SP of atypical AVNRT from the ablation site, and concluded that the anterogradesp was not located in the same area asthe retrograde SP. However, differences in the electrophysiological and anatomical properties of the SP between F/S and S/S remain unclear. The purpose of the present study was to clarify these differences of the SP between F/S and S/S. * Corresponding author. Tel: ; fax: , kmizu@med.u-toyama.ac.jp Published on behalf of the European Society of Cardiology. All rights reserved. & The Author For permissions please journals.permissions@oup.com.

2 552 Y. Nakatani et al. What s new? We evaluated differences in the electrophysiological property of the slow pathway (SP) between the fast slow form (F/S) and the slow slow form (S/S) of atypical atrioventricular nodal reentrant tachycardia (AVNRT). We evaluated anatomical differences of the SP between the F/S and the S/S of atypical AVNRT from the successful ablation site. Methods Study population Atypical AVNRT was defined when the HA interval during ventricular pacing at the same cycle length with tachycardia was 70 ms in patients with AVNRT. 1,6 During atypical AVNRT, F/S form was defined when the AH interval was,200 ms, and S/S form, the AH interval 200 ms. In the present study, the location of the earliest atrial activation site (EAA) during tachycardia was not included in the classification criteria, because the connection of the retrograde SP to atrial myocardium could vary widely. 7,8 The presence of the lower common pathway (LCP) was also not included in the classification criteria, because the relation between subforms of AVNRT and LCP remains controversial. 6,9 Patients with an accessory pathway or atrial tachycardia were excluded. Therefore, the present study included 24 patients (9 men and 15 women; mean age years) with atypical AVNRT (9 F/S and 15 S/S), who underwent electrophysiological study and catheter ablation in our institution between 2002 and The present study protocol was carried out in accordance with the Declaration of Helsinki. Written informed consent was obtained from all patients before participation. Electrophysiological study All antiarrhythmic agents had been discontinued for at least five half-lives before the study. Catheterization was performed under local anaesthesia via the right and left femoral veins and/or the left antecubital vein. Three electrode catheters were positioned at the high right atrium, the His bundle region, and the coronary sinus (CS) region, with the proximal bipole of the CS catheter positioned at the CS ostium. A 7Fr deflectable catheter with a 4 mm ablation tip (EP Technologies) was inserted through the right femoral vein for atrial mapping and catheter ablation. Bipolar intracardiac electrograms filtered between 30 and 500 Hz were simultaneously recorded and stored digitally on the CardioLab system (Prucka Engineering) with a 12-lead surface electrocardiogram. Stimuli were delivered from a programmable stimulator (Nihon-Koden SEC3102) as rectangular pulses of 2 ms duration and twice the diastolic threshold. The diagnosis of AVNRT was made on the basis of the standard criteria. 10 Atrioventricular reciprocating tachycardia was excluded when the tachycardia was not reset by ventricular extrastimulation delivered, while the His bundle was refractory. Atrial tachycardia was excluded when the tachycardia was induced by ventricular pacing with a V A V sequence, and the tachycardia was reproducibly terminated with ventricular extrastimulation not reaching the atrium. Anterograde dual-av nodal physiology was identified by a sudden increase in the AH interval of 50 ms with a 10 ms decrement in atrial extrastimulus coupling interval. Retrograde dual-av nodal pathway physiology was identified by a shift in EAA from the His bundle region to the CS region in response to ventricular extrastimulation. Retrograde AV nodal conduction was judged as over the FP and the SP when the HA interval during ventricular pacing was,70 and 70 ms, respectively. 1,6 Effective refractory period (ERP) of the FP and the SP was evaluated. Conduction time through LCP was calculated by subtracting HA interval during the tachycardia from that during the ventricular pacing at the same cycle length with the tachycardia. Lower common pathway was considered to exist when LCP conduction time was 15 ms. 6 Earliest atrial activation site and HA (CS-His) Earliest atrial activation site during the tachycardia and ventricular pacing was localized by mapping the right side of the interatrial septum and the CS using the ablation catheter. To clarify the electroanatomical location of EAA, HA (CS-His) during the tachycardia was measured by subtracting the shortest HA interval in the His bundle region (HA His ) from the shortest HA interval in the CS region (HA CS )(Figure 1). Radiofrequency catheter ablation of the slow pathway Catheter ablation was performed with a 550 khz unmodulated radiofrequency (RF) current from a generator with temperature monitoring (EP Technologies). The RF energy was applied in a temperaturecontrolled mode, with an upper temperature limit of 558C, maximal power output of 30 W. If an accelerated junctional rhythm was observed, a 40 s RF application was delivered. Radiofrequency current was delivered at EAA during tachycardia and ventricular pacing, or at the recording site of slow potentials 11 during sinus rhythm. Induction of tachycardia and evaluation of AV nodal conduction properties were attempted immediately after each application of the RF current. Elimination of anterograde SP conduction was achieved as the anterograde dual-av nodal pathway physiology that had been observed before application of the RF Figure 1 HA (CS-His) and A/V ratio. Dashed arrow (A) indicates retrograde SP conduction fromthe His bundle (His) to the EAA, and solid arrows (B and C) indicate intra-atrial conduction from EAA to the His electrode and the CS electrode during the tachycardia. The HA intervals in the His region (HA His ) and the CS region (HA CS ) reflect the conduction time from the His to the His electrode (A + B) and the CS electrode (A + C). Because HA (CS-His) is measured by subtracting HA His from HA CS (C 2 B), it increases when EAA approaches to the His region and decreases when EAA approaches to the CS region. The A/V ratio increases in the atrial side and decreases in the ventricular side. AV node, atrioventricular node; CS os, CS ostium; TA, tricuspid annulus.

3 Slow pathway of atypical AVNRT 553 current was eliminated. Elimination of retrograde SP conduction was achieved as retrograde AV nodal conduction with HA 70 ms was eliminated. When elimination of the anterograde SP and/or the retrograde SP was observed after application of the RF current, the location of the ablation site was assessed by evaluating the ratio of the amplitudes of atrial and ventricular potential (A/V ratio) recorded before application of the RF current (Figure 1). Statistical analysis The values are presented as the mean + standard deviation together with 95% confidence intervals. The significance of any differences between the two groups was analysed with the Student s t-test for continuous variables and with Fisher s exact probability test for categorical variables. The significance of any differences among the multiple groups was analysed with one-way analysis of variance (ANOVA). If one-way ANOVA revealed a significant difference, a post hoc test with Bonferroni-adjusted pairwise comparisons was performed. A P value of,0.05 was accepted as statistically significant. Results Clinical and electrophysiological characteristics The mean age and the gender did not differ between the groups of F/S and S/S (Table 1). During sinus rhythm, AH interval was significantly longer in the S/S group compared with the F/S group; however, HV interval did not differ between the two groups. All patients of S/S had anterograde SP but only five of nine F/S patients did so (P, 0.05). Five F/S patients and six S/S patients had retrograde FP, and all patients in each group had retrograde SP. Effective refractory period of anterograde FP, anterograde SP, and retrograde FP did not differ between the two groups. However, ERP of retrograde SP was Table 1 Comparison of clinical and electrophysiological data between F/S and S/S significantly longer in S/S than in F/S. The tachycardia cycle length and AH interval during tachycardia were significantly longer in S/S than in F/S, and the HA intervals during tachycardia and ventricular pacing were significantly shorter in S/S than in F/S. Lower common pathway was observed in 7 patients (78%) of F/S and 11 patients (73%) of S/S, and LCP conduction time was not different between the two groups. Earliest atrial activation site and HA (CS-His) Representative cases for evaluation of HA (CS-His) were demonstrated in Figures 2 4. Earliest atrial activation site of F/S was located at the mid-interatrial septum in four patients and the inferior interatrial septum in five patients. Earliest atrial activation site of S/S was observed at the mid-interatrial septum in five patients and the inferior interatrial septum in nine patients. HA (CS-His) was not different between the two groups ( in F/S vs ms in S/S, NS) (Figure 5). Catheter ablation of the slow pathway After the diagnosis of AVNRT, catheter ablation was performed in all 24 patients. In F/S, RF energy was delivered at EAA in seven patients and at the slow potential recording site in two patients. In S/S, RF energy was delivered at EAA in seven patients and at the slow potential recording site in eight patients. In F/S, the retrograde SP conduction was eliminated in six F/S patients during RF application. In S/S patients, the anterograde and retrograde SP conduction was separately eliminated in two and five patients, respectively, and the anterograde and retrograde SP conduction was simultaneously eliminated in five patients during RF application. In three patients in each group, RF application did not eliminate either anterograde or retrograde SP. Fast slow form (n 5 9) Slow slow form (n 5 15) P value... Age (years) NS Sex, female gender 4 (44%) 11 (73%) NS AH interval during sinus rhythm (ms) P, 0.05 HV interval during sinus rhythm (ms) NS Existence of anterograde SP 5 (56%) 15 (100%) P, 0.05 Existence of retrograde FP 5 (56%) 6 (40%) NS Existence of retrograde SP 9 (100%) 15 (100%) NS ERP of anterograde FP (ms) NS ERP of anterograde SP (ms) NS ERP of retrograde FP (ms) NS ERP of retrograde SP (ms) P, 0.05 Tachycardia cycle length (ms) P, 0.01 AH interval during tachycardia (ms) P, 0.01 HA interval during tachycardia (ms) P, 0.01 HA interval during ventricular pacing (ms) P, 0.01 LCP (%) 7 (78%) 11 (73%) NS LCP conduction time (ms) NS SP, slow pathway; FP, fast pathway; ERP, effective refractory period; LCP, lower common pathway.

4 554 Y. Nakatani et al. Figure 2 A representative case of the F/S tachycardia. Three surface electrocardiographic leads (I, avf, and V1) and intracardiac electrograms are shown. HA His,HA CS, and HA (CS-His) were 319, 300, and 219 ms, respectively, during the tachycardia (A). The A/V ratio of the ablation catheter (ABL) at EAA was 0.30 (B). Right (RAO) and left (LAO) anterior oblique fluoroscopic images demonstrate the position of ABL (C). Radiofrequency ablation in this site successfully eliminated the retrograde SP conduction. HRA, high right atrium electrogram/electrode; HIS, His electrogram/ electrode; CS, coronary sinus electrogram/electrode. Figure 3 A representative case of the S/S tachycardia. Tachycardia (A). The A/V ratio of ABL located at the SP potential recording site was 0.10 (B). Right (RAO) and left (LAO) anterior oblique fluoroscopic images demonstrate the position of ABL located anterior to the CS os (C). Radiofrequency ablation in this site successfully eliminated both the anterograde and retrograde SP conduction. HRA, high right atrium electrogram/electrode; HIS, his electrogram/electrode; CS, coronary sinus electrogram/electrode.

5 Slow pathway of atypical AVNRT 555 Figure 4 Another representative case of S/S tachycardia. The A/V ratio of ABL at EAA was 0.83 during the tachycardia (A). Right (RAO) and left (LAO) anterior oblique fluoroscopic images demonstrate the position of ABL located at the CS os (B). After radiofrequency ablation in this site, the retrograde SP conduction was separately eliminated. HRA, high right atrium electrogram/electrode; HIS, His electrogram/electrode; CS, coronary sinus electrogram/electrode. HA (CS-His) (ms) F/S S/S Figure 5 Comparison of HA (CS-His) between the F/S and the S/S tachycardia. HA (CS-His) was not different between the two groups. Data are mean + standard deviation. NS evaluated (Figures 2 4). To assess whether the ablation point may involve anterograde SP, S/S cases were divided into two groups, patients in whom the anterograde SP was separately or both anterograde and retrograde SPs were eliminated (Figure 3) (S/S asp-e, n ¼ 7) and those in whom the retrograde SP was separately eliminated with preserved anterograde SP (Figure 4) (S/S asp-p, n ¼ 5) after RF application. The A/V ratio was not different between F/S and S/S asp-e ( vs ms, NS); however, it was significantly greater in S/S asp-p compared with F/S and S/S asp-e ( ms, P, 0.01 vs. F/S and S/S asp-e) (Figure 6). Discussion Major findings The major findings of the presentstudyare as follows. First, ERPof the retrograde SP was longer in S/S than in F/S. Secondly, the HA interval during the tachycardia was significantly shorter in S/S than in F/S. Thirdly, HA (CS-His) was not different between F/S and S/S. Fourthly, the location of the ablation site in which retrograde limb of F/S was eliminated was similar to that in which the anterograde limb of S/S was eliminated. The ratio of the amplitudes of atrial and ventricular potential In the patients in which catheter ablation was successfully performed (6 F/S and 12 S/S), the A/V ratio at the successful ablation site was Previous studies regarding atrioventricular nodal pathways The compact AV node is considered to be connected with the atrial myocardium through the FP and the SP; 1,12 however, previous studies 11,13 suggested the presence of additional AV nodal pathways. Wu et al. 14 suggested that intermediate pathway (IP), which had

6 556 Y. Nakatani et al. A/V ratio 1.5 NS P < 0.01 P < 0.01? LIE Fast slow Compact AV node His RIE LIE Slow slow Compact AV node His RIE? TA TA 1.0 CS os CS os F/S S/S asp-e S/S asp-p Figure 6 Comparison of the A/V ratio among the F/S and the S/S with anterograde SP being eliminated (S/S asp-e) and being preserved (S/S asp-p). The A/V ratio was significantly larger in S/S asp-p compared with F/S and S/S asp-e ( vs and ms, respectively, P, 0.01). Data are mean+standard deviation. intermediate electrophysiological properties between the FP and the SP, was included in the reentrant circuit of S/S. In the present study, ERP of the retrograde SP of S/S was significantly longer than that of the retrograde SP of F/S. Moreover, the HA interval during the tachycardia was significantly shorter in S/S than in F/S. HA (CS-His) was not different between the two groups. This result suggests that the distance from the His bundle to the connection site of the retrograde limb to the atrial myocardium did not differ between F/S and S/S. Accordingly, the differences in the HA interval between the two forms could be resulted from the difference in the conduction velocity of the retrograde limb of the reentrant circuit, and the retrograde limb of S/S may consist of IP. The anatomical substrates of the AV nodal pathways are still unknown. However, Inoue and Becker 15 suggested that the right and left inferior extension of the compact AV node may form the AV nodal pathway. They also demonstrated that the ablation site that altered or eliminated SP conduction involved the rightward inferior extension of the AV node. 16 These results suggest that the SP consists of the rightward posterior extension. Moreover, previous studies 14,15,17 demonstrated that the IP consisted of the leftward posterior extension. This hypothesis is supported by mapping studies in rabbit 18 and canine 19 hearts. In the present study, the retrograde limb of F/S was eliminated by RF energy delivered to the site with the smaller A/V ratio, indicating that the ablation site was located to the ventricular side of the triangle of Koch. Therefore, the retrograde limb of F/S may be mediated through right inferior extension. 17 In contrast, the retrograde limb of S/S was eliminated by RF energy delivered to the site with the greater A/V ratio, which Fast pathway Slow pathway Intermediate pathway Figure 7 The reentrant circuits of atypical AVNRT. In F/S tachycardia, retrograde conduction is mediated through the SP, which runs ventricular side of the triangle of Koch. In S/S tachycardia, anterograde conduction is mediated through the SP and retrograde conduction through the intermediate pathway (IP), which runs atrial side of the triangle of Koch. Fast slow form may utilize the IP but not fast pathway (FP) for the anterograde limb of the reentrant circuit. LIE, left inferior extension of the atrioventricular node; RIE, right inferior extension of the atrioventricular node; AV node, atrioventricular node; CS os, CS ostium; TA, tricuspid annulus. indicates that the ablation site was located on the atrial side of the triangle of Koch. Therefore, the retrograde limb of S/S may be mediated through left inferior extension. 17 Accordingly, the retrograde conduction of F/S and S/S could be mediated by the SP and the IP, respectively. The anterograde limb of S/S was eliminated at the site with the smaller A/V ratio; therefore, the anterograde conduction of S/S is likely to be mediated through the SP similar to the retrograde limb of F/S. Proposed reentrant circuits of atypical atrioventricular nodal reentrant tachycardias The proposed reentrant circuits of atypical AVNRTs are presented in Figure 7. In the F/S form, retrograde conduction is mediated by the SP, which runs through the ventricular side of the triangle of Koch. In the S/S form, anterograde conduction is mediated by the SP and retrograde conduction is mediated by the IP which runs through the atrial side of the triangle of Koch. In some cases with S/S, in whom anterograde and retrograde conduction were simultaneously ablated by RF energy delivered to a single site, SP and IP could be located close to each other. The substrate of the anterograde conduction of F/S was not evaluated in the present study. Fast slow form has been previously thought to have the reverse direction of the reentrant circuit of S/F. 3 However, most cases of F/S had LCP in the present study, in contrast to the previous finding that most S/F cases did not have LCP. 1,6 Therefore, F/S may not utilize FP but IP for the anterograde limb of the reentrant circuit, because FP conduction has the superior input to the compact AV node, 20 and the superior input is closer to

7 Slow pathway of atypical AVNRT 557 the His bundle compared with the inferior input. 1 However, further investigation is needed to draw a definite conclusion. Study limitations The present study was limited in several ways. First, the numberof the patients included in the present study was too small to draw a definite conclusion. Secondly, the recording and pacing sites were limited to the right atrium. A previous study 21 reported that successful ablation of the left-sided SP was performed in S/F cases, and another study 22 reported atypical AVNRT with eccentric retrograde left-sided activation. The left atrial myocardium may form an essential component of atypical AVNRTs. Thirdly, RF energy was not delivered to the CS in the present study. Accordingly, it was unclear whether the reentrant circuit of atypical AVNRT contains the CS musculature. Finally, RF energy was delivered several times in some patients. This may have influenced the results of the present study. However, the induction of tachycardia with the evaluation of AV nodal conduction properties was attempted immediately after each application of RF current. Conclusions The electrophysiological properties of the retrograde SP differ between F/S and S/S. The anatomical location of the retrograde SP of F/S is similar to the anterograde SP of S/S, but not the retrograde SP of S/S. Therefore, F/S utilizes the SP for the retrograde conduction, and that S/S utilizes the SP for the anterograde conduction and the IP for the retrograde conduction. Conflict of interest: none declared. References 1. Heidbüchel H, Jackman WM. Characterization of subforms of AV nodal reentrant tachycardia. Europace 2004;6: Katritsis DG, Josephson ME. Classification of electrophysiological types of atrioventricular nodal re-entrant tachycardia: a reappraisal. Europace 2013; Epub ahead of print. 3. Yamabe H, Shimasaki Y, Honda O, Kimura Y, Hokamura Y. 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