Antegrade slow pathway mapping of typical atrioventricular nodal reentrant tachycardia based on direct slow pathway capture

Abstract Background Radiofrequency (RF) ablation of typical atrioventricular nodal reentrant tachycardia (tAVNRT) is performed without revealing out the location of antegrade slow pathway (ASp). In this study, we studied a new electrophysiological method of identifying the site of ASp. Methods This study included 19 patients. Repeated series of very high‐output single extrastimulations (VhoSESts) were delivered at the anatomical slow pathway region during tAVNRT. Tachycardia cycle length (TCL), coupling interval (CI), and return cycle (RC) were measured and the prematurity of VhoSESts [ΔPM (= TCL – CI)] and the prolongation of RCs [ΔPL (= RC – TCL)] were calculated. Pacing sites were classified into two categories: (i) ASp capture sites [DSPC(+) sites], where two different RCs were shown, and ASp non‐capture sites [DSPC(‐) sites], where only one RC was shown. RF ablation was performed at DSPC(+) sites and/or sites with catheter‐induced mechanical trauma (CIMT) to ASp. Results DSPC(+) sites were shown in 13 patients (68%). RF ablation was successful in all patients without any degree of atrioventricular block nor recurrence. Total number of RF applications was 1.8 ± 1.1. Minimal distance between successful ablation sites and DSPC(+)/CIMT sites and His bundle (HB) electrogram recording sites was 1.9 ± 0.8 mm and 19.8 ± 6.1 mm, respectively. ΔPL of more than 92.5 ms, ΔPL/TCL of more than 0.286, and ΔPL/ΔPM of more than 1.565 could identify ASp with sensitivity of 100%, 91.1%, and 88.9% and specificity of 92.9%, 97.0%, and 97.6%, respectively. Conclusions Sites with ASp capture and CIMT were close to successful ablation sites and could be useful indicators of tAVNRT ablation.


| Hypothesized model of tAVNRT
At first, the following three preconditions were set: (i) Conduction curve of the ASp corresponding to the extrastimulations with a gradual shortening of the coupling interval exhibits a sigmoid curve (illustrated in Figure 1A and patients with sigmoid curves in Figure S1).
(ii) Conduction properties of ASp, including conduction velocity, conduction delay, and refractory period, are uniform over the entire area of the ASp (illustrated in Figure 2).
(iii) Reentrant circuit of tAVNRT contains atrial muscle (illustrated in Figure 1B). Figure 1B (1) TCL = a + b + c + d + e F I G U R E 1 Schematic presentation of the hypothesized model of tAVNRT (A, B), effect of a VhoSESt during tAVNRT (C), and the order of manipulating Abl catheter (D). A: ASp conduction curve is hypothesized to be a sigmoid conduction curve. B: P1, P2, P3, P4, and P5 were located on the circuit of tAVNRT and P6 was located outside of the tAVNRT circuit. TCL was defined as the summation of the conduction time of a, b, c, d, and e. C: TCL, CI, and RC(n + 1) were measured and ΔPM and ΔPL were calculated. The electrograms drawn by the black broken line show the expected electrogram location in a case without VhoSESt. D: Abl catheter was moved sequentially from ① to ⑧ until a successful ablation was achieved. Asp, antegrade slow pathway; AFp, antegrade fast pathway; RFp, retrograde fast pathway; AVN, atrioventricular node; Abl, ablation; VhoSESt, very high-output single extrastimulation; P1, site of RA capture by a VhoSESt delivered from Abl catheter; P2, junctional site between RA and ASp; P3, site of ASp capture by a VhoSESt delivered from Abl catheter; P4, turnaround site between ASp and RFp in AVN; P5, junctional site between RFp and RA; P6, any point in atrium and coronary sinus (CS) located away from ASp; HB, His bundle; TCL, tachycardia cycle length; CI, coupling interval, RC, return cycle; RC(n) = interval between VhoSESt and onset of QRS wave; RC(n + 1) = interval between VhoSESt and onset of A wave recorded at Abl catheter; Int(n − 1, n) = interval between the onset of QRS wave of n − 1 and n beats; Int(n, n + 1) = interval between the onset of QRS wave of n and n + 1 beats; ΔPM, prematurity of VhoSESts [= TCL − CI]; ΔPL, prolongation of return cycle [= RC(n + 1) − TCL]; TCL, tachycardia cycle length; TT, tendon of Todaro; TA, tricuspid annulus; CSos, CS ostium

| Effects of VhoSESts on the hypothesized model of tAVNRT
2.2.1 | In the case of VhoSESts delivered following the effective refractory period (ERP) of ASp(n) between n − 1 and n beats (areas ⑦, ⑧, and ⑨ in Figure 3B) Figure 1C using a ladder diagram illustrates the effects of VhoSESts on the hypothesized model of tAVNRT. During tAVNRT, a VhoSESt was delivered following the ERP of ASp(n) between n − 1 and n beats (areas ⑦, ⑧, and ⑨ in Figure 3B). TCL, coupling interval F I G U R E 2 Schematic presentation of RC(n + 1) in the cases of ASp non-capture with a ΔPM of x (A), of ASp non-capture with a ΔPM of x + ε (B), and of ASp capture with a ΔPM of x (C). A: RCNC(x) = TCL + α and ΔPLNC(x) = α. B: RCNC(x + ε) = TCL + β and ΔPLNC(x + ε) = β. C: RCC(x) = TCL + βε = RCNC(x + ε)ε and ΔPLNC(x) = βε = ΔPLNC(x + ε)ε. RCNC(x) and RCNC(x + ε) = RC in the cases of ASp non-capture with a ΔPM of x and x + ε, respectively; ΔPLNC(x) and ΔPLNC(x + ε) = ΔPL in the cases of ASp non-capture with a ΔPM of x and x + ε, respectively; RCC(x) and ΔPLC(x) = RC and ΔPL in case of ASp capture with a ΔPM of x. The other abbreviations are the same as those given in Figure 1 F I G U R E 3 Schematic presentation of the relationship between ASp capture and ASp non-capture in the sigmoid conduction curve of ΔPLNC in the ΔPM-ΔPL coordinate system (A) and the relationship of the anatomical location of the pacing site of ASp, ΔPM, and ΔDSPC in response to a VhoSESt delivered between n − 1 and n beats (B). A: ΔPLC(x) (point C) was created by shifting ΔPLNC(x + ε) (point B) leftward then downward by the same amount of ε. B: The area between n − 1 and n beats was divided into nine areas based on the pacing site along the ASp, ΔPM, and ERP of RA and ASp. The effects of VhoSESts in each area were shown below. A positive value of ΔDSPC(n + 1) with a prolongation of Int(n, n + 1) was only shown in area ⑧ and was mostly confined to dASp. This area was the target of this study. The blue circle in area ⑧ showed the maximum positive value of ΔDSPC(n + 1). The pink star in area ② was the estimated pacing site in the previous study. †: the change in RC(n + 1) and ΔDSPC(n + 1) depended on the change in Int(n − 1, n). ‡: the change in RC(n + 1) and ΔDSPC(n + 1) depended on the change in Int(n − 1, n). §: the change of Int(n, n + 1) depended on the change in Int(n − 1, n). pASp, mASp, and dASp, proximal, middle, and distal part of the ASp, respectively; ERP, effective refractory period; RA-ASp-J, junctional site between the RA and ASp; Term, termination of tAVNRT; ΔDSPC(n) = Int(n − 1, n)C(x) − Int(n − 1, n)NC(x); ΔDSPC(n + 1) = RCC(x) − RCNC(x) = ΔPLC(x) − ΔPLNC(x) = Int(n, n + 1)C(x) − Int(n, n + 1)NC(x) (except for area ⑤). U, unchanged; S, shortening; P, prolongation; NA = not assessed; N, no; Y, yes. The other abbreviations are the same as those given in Figures 1 and 2 (CI), and return cycle (RC) were measured and the prematurity of VhoSESt (ΔPM) and prolongation of RC(n + 1) (ΔPL) were calculated as follows: 2.2.2 | Effects of VhoSESts delivered away from the ASp ( Figure 1B Therefore, RC(n + 1)s [= Int(n, n + 1) + ΔPM], corresponding to the same series of VhoSESts with the same CI at the same pacing site, changed between ASp(n + 1) non-capture [only RA (P1) capture] and both ASp(n + 1) (P3: HPT) and RA (P1: LPT) capture, and exhibited two discrete RC(n + 1)s, because conduction paths were different between those two (shown in Figure 2A Here, Int(n, n + 1): interval of QRS waves between n and n + 1 beats.

| Effects of VhoSESts delivered along the ASp
As shown in Figure 2A Here, α (= αa + αb + αc + αd + αe) was the conduction delay made by a VhoSESt with a ΔPM of x.
NC(x): Non-Capture of the ASp with a ΔPM of x.

As shown in
As shown in Figure 3A , on the sigmoid conduction curve of ΔPLNC on the ΔPM-ΔPL plane, points A, B, and C showed ΔPLNC(x), ΔPLNC(x + ε), and ΔPLC(x), respectively. ΔPLC(x) (point C) was made by moving ΔPLNC(x + ε) (point B) leftward then downward by the same amount of ε, or moving ΔPLNC(x + ε) (point B) parallel to the straight line of ΔPL = ΔPM as a value of 2 1/2 ε.
The amount of ε became larger when Abl catheter was moved gradually from P2 (distal part of the ASp; dASp) to P4 (proximal part of the ASp; pASp) (shown in Figures 2C and 3B). Therefore, the amount of ε indicated the location of Abl catheter along the ASp. When the condition of x = x1 and ε = x3 -x1 was met, the value of ΔDSPC(n + 1) became the maximum (shown as a blue circle at area ⑧ in Figure 3B).
Here, x1: the smaller value of ΔPM at the point where the slope of the sigmoid conduction curve of ΔPLNC was 1.

| Relationship between the value of ΔDSPC(n + 1) and pacing site
As illustrated in the ladder diagram 3B, the value of ΔDSPC(n + 1) was positive in area ⑧ and negative in areas ⑦ and ⑨. When the pacing site showed a visually identifiable large positive value of ΔDSPC(n + 1), the pacing site was suggested to be located mostly at dASp around the blue circle at area ⑧ in Figure 3B. 2.2.6 | In the case of VhoSESts delivered ahead of the ERP of ASp between n − 1 and n beats (areas ②, ③, and ⑤ in Figure 3B) As shown in Figure 3B, if repeated series of VhoSESts were delivered ahead of the ERP of ASp(n) between n − 1 and n beats (areas ②, ③, and ⑤ in Figure 3B), capture or non-capture of ASp(n) occurred and Int(n − 1, n) and RC(n) were changed. When ASp(n) was captured at areas ② and ③, where RA could not be captured because of the ERP of RA, Int(n − 1, n) and RC(n) were shortened and extended, respectively. Then, ΔDSPC(n + 1) and RC(n + 1) were shortened and extended as much as the shortening and extension of Int(n − 1, n), or RC(n), respectively, because Int(n, n + 1) was equal to TCL and was unchanged in both cases. At area ⑤, capture of ASp(n) shortened Int(n − 1, n) and RC(n) and therefore extended Int(n, n + 1). However, RC(n + 1), corresponding to a VhoSESt with the same CI at the same pacing site, had a single extended value, or ΔDSPC(n + 1) = 0, because RC(n + 1) of area ⑤ was created by RA capture, not by ASp(n) capture.

| Patients
This study was a retrospective review of case series of 19 consecutive patients (6 men and 13 women, 61 ± 18 years, range 20 to 89 years) undergoing RF ablation of tAVNRT from June 2016 to September 2018. Written informed consent was obtained from all patients before the procedure. The study protocol was approved by the Research Ethics Committee of Tokushima University Hospital.

| Electrophysiological study and catheter ablation
All patients underwent electrophysiological study in a fasting, unse-  Figure 1D.
(iii) Pacing output of VhoSESt from Abl catheter was set at 10-20 V/1 ms or at 20 mA/1 ms (iv) Delivery of VhoSESts was set at a timing that was earlier than the timing of the HB electrogram on HB catheter, but the precedence of which was less than 40 ms in order to exclude the possibility to retrograde intrusion of the excitation wave into the AVN when VhoSESts captured RV.
(v) The number of VhoSESts at each pacing site was set at 10-15 times.
(vi) If VhoSESts did not exhibit two visually discrete RCs with ΔDSPC(n + 1) of more than 50 ms, then Abl catheter was moved to the next pacing site in accordance with the order shown in Figure 1D.
(vii) If VhoSESts exhibited two visually discrete RCs with ΔDSPC(n + 1) of more than 50 ms, then RF ablation was performed at that site.

(viii)
If CIMT1 occurred, the sites of CIMT1 were stored onto 3D map with reference to the fluoroscopy and CARTOREPLY in the case of using the CARTO system. Then, repeated VhoSESts to seek the sites of ASp capture were performed around these sites. If VhoSESts exhibited two visually discrete RCs, then RF ablation was performed around these sites, or if CIMT2-4 occurred during the manipulation of Abl catheter and tAVNRT was no longer induced or sustained, then two to three RF applications were performed at and around the CIMT sites.
(ix) If Sn, S0, or S1 was achieved even during isoproterenol infusion at a rate of 1 μg/min, RF ablation was considered to be successful. If F2 or Ft still remained, VhoSESts were continued to seek the sites of ASp capture or CIMT2-4, by changing the pacing site in accordance with the order shown in Figure 1D until successful RF ablation was achieved.
Here, CIMT was classified by the degree of ASp conduction disturbance as follows: 1. CIMT1: tachycardia was induced and sustained with prolongation of TCL.
2. CIMT2: tachycardia was induced but the sustenance of the tachycardia was reduced.

| Statistics
Continuous variables were expressed as mean ± SD, and those variables were compared using the Student's t-test. Sensitivity, specificity, and positive and negative predictive values were calculated using standard methods. Optimal cut-off values of the continuous variables to identify the ASp were determined using receiver operating characteristic (ROC) curve analysis. The performance of the pacing studies was evaluated according to the areas under the ROC curves.
A p-value < 0.05 was considered statistically significant.

| Pacing study for the identification of the ASp
All of the settings of the pacing output of 10-20 V/1 ms and

| Condition showing more than 50 ms of ΔDSPC(n + 1)
In order to make ΔDSPC(n + 1) be identified visually, ΔDSPC(n + 1) should be more than 50 ms in response to ΔPMs with a dispersion of less than 10 ms We selected VhoSESts with ΔDSPC(n + 1)s of more than 50 ms in response to ΔPMs with a dispersion of less than 10 ms (if   in the case of ASp non-capture was 0.9 ± 0.2, and which was slightly less than 1. The sensitivity and specificity of ΔPL of more than 92.5 ms, ΔPL/TCL of more than 0.286, and ΔPL/ΔPM of more than 1.565 for the identification of the ASp were 100% and 91.1%, 88.9% and 92.9%, and 97.0% and 97.6%, respectively ( Figure 4; Tables 2 and 3).

| Catheter ablation
Catheter 1.8 ± 0.9 mm. CIMT1 sites were almost the same as DSPC(+) sites. The minimal distance between the ineffective ablation sites and DSPC(+) sites was 8.1 ± 8.0 mm and was significantly larger than that between the effective ablation sites and DSPC(+) sites (1.9 ± 0.8 mm) (P = .01).
The minimal distance between the successful ablation sites and HB electrogram recording sites was 19.8 ± 6.1 mm (20.3 ± 6.4 mm in the patients with ASp capture and 18.6 ± 5.6 mm with CIMT2-4, respectively). There were no cases with any degree of AVB or recurrence of tAVNRT during the follow-up period of 33 ± 8 months (Table 1).

| Case presentation
In Figure

| Main findings
In the present study, we showed that all of the sites with ASp capture, CIMT, and successful ablation were adjacent to each other and indicated the location of ASp. Our protocol was successful for the treatment of tAVNRT with a low number of both effective and ineffective RF applications without any degree of AVB or recurrence. A visually identifiable difference in ΔDSPC of more than 50 ms was shown in all patients with ASp capture. About one-third of the patients had CIMT2-4, but were successfully ablated according to a systematic manipulation of Abl catheter and 3D mapping system (especially using CARTOREPLAY).

| Previous studies
Electrophysiological phenomenon of ASp capture has been reported in only two case reports 2,3 . In those papers, (i) resetting of tAVNRT with the shortening of Int(n, n-1) by capturing only the ASp in response to VhoSESts delivered at a timing of the ERP of both RA and RV and (ii) termination of tAVNRT according to the conduction block in the ASp in response to VhoSESts delivered at a timing of the ERP of both the RA and RV were reported. These ASp capture sites were spatially away from the HB recording sites, and catheter ablation was successful at these sites. This electrophysiological phenomena reported in these previous studies could also be explained by our model (Figure 3B), and the sites of ASp capture/successful ablation were located at the pink star in area ② in Figure 3B. Only with the electrophysiological information, previous reports could only indicate that the pacing sites were located near the ASp, but could not indicate any information about which parts of the ASp were captured, because both the termination of tAVNRT and shortening of Int(n, n-1) with the same extent could be shown not only in dASp but also in pASp and mASp in area ② of Figure 3B. And whether or not ASp capture sites were spatially away from the HB recording sites, which did not always mean dASp, was only judged by fluoroscopy or 3D map. Our method, only electrophysiologically, could identify dASp by finding out two discrete RCs with ΔDSPC of more than 50 ms Moreover, the minimal distance between the successful ablation sites and HB electrogram recording sites measured in this study (19.8 ± 6.1 mm) was longer than that in the previous study of a combined anatomical and electrogram-guided approach (11.6 ± 4.7 mm), and this also suggested that our method could identify dASp. 6

| Sigmoid conduction property of ASp
Some previous studies actually showed a sigmoid AVN conduction curve of both the ASp [11][12][13][14][15][16][17][18][19] and antegrade fast pathway (AFp). 20 As shown in Figure S9, among the 13 patients showing the conduction curve of both ASp capture and ASp non-capture, three patients (23%) exhibited the sigmoid conduction curve, and all sigmoid conduction curves were only demonstrated in the conduction curves of ASp capture. Therefore, the sigmoid conduction curves could only be seen when the extrastimulations were delivered with a quite short coupling interval and that this could be a reason why the sigmoid conduction curves could be seen only rarely. Moreover, as shown in Figure S5, if ASp conduction curve is the exponential curve, as is generally believed, the slope of ASp conduction curve is more than 1 when the value of x is more than x1. Therefore, if the value of x is more than x1 and VhoSESts are delivered gradually approaching to pASp from dASp, then ΔPLC(x) becomes monotonically larger ( Figure S5A). In patient 17 (shown in Figure S6), most proximal pacing site ④ showed the smallest ΔPLC, and this could not be explained by the exponential curve model, but can be explained by the sigmoid curve model ( Figure   S5B). However, there was the possibility that AVN conduction curve showed both the exponential and sigmoid conduction curves, and further study will be needed.

| Application of this method
This method also could be applied to find out the ASp in patients with S/S AVNRT and we experienced two successful cases (these patients were not included in this study because their tachycardia was not typical AVNRT, data are shown in S1). However, this method cannot be applied to find out the RSp in patients with F/S AVNRT because RV can be captured at this timing and the tachycardia can be reset by the excitation wave intruding into the circuit retrogradely.

| Limitations
Our institute is a low volume center and has a small number of patients with tAVNRT. A multicenter large volume prospective study will be needed.
Our study and the previous reports could only give explicable information about areas ② and ⑧ in Figure 3B, but gave no information about the other areas. Further study will be needed.
In this study, the conduction property of the ASp was hypothesized to be uniform over the entire area of the ASp, but this is not exactly correct, because the atrioventricular conducting system has a multilayer structure. 21,22 However, the exact conduction property of each layer and interlayer is uncertain and controversial. Therefore, the morphology of each area in Figure 3B is likely to be changed.
In this study, all ASps were located at the anatomical slow pathway region. However, slow pathway is sometimes located at the mitral annulus, tricuspid annulus, and non-coronary cusp of Valsalva. [23][24][25][26][27] In such cases, whether or not our method worked well was uncertain.
In this study, none of the tAVNRTs had VA conduction block.
However, the tAVNRTs sometimes had VA block according to the conduction block at the upper common pathway. [28][29][30] In such cases, the tachycardia circuit contained no atrial muscle and whether or not our method worked well was uncertain.
In the anatomical slow pathway region, the autonomic nervous system has been reported to be captured sometimes and to change the conduction property of the ASp or AFp. 19,31 However, in this study, tAVNRTs were terminated only when ΔPM was large and RCs were progressively larger when ΔPM gradually became larger. Therefore, the termination and prolongation had a clear relationship with ΔPM and effects of the autonomic nervous system were uncertain.
ASp capture was shown not only during the tachycardia but also during the induction of tachycardia (data not shown). Using ASp capture during the induction of tachycardia, we may detect the ASp of patients with CIMT2-3 and may perform basic animal study of ASp capture. Further study will be needed.

| CON CLUS IONS
Sites with ASp capture and CIMT were close to successful ablation sites and could be useful indicators of tAVNRT ablation.

ACK N OWLED G M ENTS
The authors thank Mr John Martin and Ms Michiko Tobiume for their linguistic assistance with this manuscript.

CO N FLI C T O F I NTE R E S T
Authors declare no conflict of interests for this article.

D I SCLOS U R E S
The protocol for this research project has been approved by