The First Evaluation of Remote Magnetic Navigation-Guided Pediatric Ventricular Arrhythmia Ablation

Catheter ablation (CA) is an important treatment option for ventricular arrhythmias (VA) in pediatric cardiology. Currently, various CA techniques are available, including remote magnetic navigation (RMN)-guided radiofrequency (RF) ablation. However, no studies evaluate RMN-guided ablative therapy outcomes in children with VA yet. This study aimed to compare procedural and long-term outcomes between RMN-guided and manual (MAN)-guided VA ablation in children. This single-center, retrospective study included all CA procedures for VA performed in children with or without structural heart disease from 2008 until 2020. Two study groups were defined by CA technique: RMN or MAN. Primary outcome was recurrence of VA. Baseline clinical, procedural and safety data were also evaluated. This study included 22 patients, who underwent 30 procedures, with a median age of 15 (IQR 14–17; range 1–17) years and a mean weight of 57 ± 20 kg. In total, 14 procedures were performed using RMN and 16 using MAN (22 first and 8 redo procedures). Regarding first procedures, recurrence rates were significantly lower in RMN compared to MAN (20% versus 67%, P = 0.029), at a mean follow-up of 5.2 ± 3.0 years. Moreover, fluoroscopy dosages were significantly lower in RMN compared to MAN [20 (IQR 14–54) versus 48 (IQR 38–62) mGy, P = 0.043]. In total, 20 patients (91%) were free of VA following their final ablation procedure. This is the first study to investigate the use of RMN in pediatric VA ablation. RMN showed improved outcomes compared to MAN, resulting in lower VA recurrence and reduced fluoroscopy exposure.


Introduction
Ventricular tachycardia (VT) and premature ventricular contractions (PVC) are less common rhythm disorders than supraventricular arrhythmias in children with normal cardiac anatomy [1,2]. Generally originating with an idiopathic etiology, they usually have a benign course with spontaneous resolvement of VA. However, in some cases untreated idiopathic ventricular arrhythmia (VA) can be associated with impaired quality of life, substantial morbidity-including hemodynamic deterioration and ventricular dysfunctionand rarely mortality [3][4][5][6][7].
Catheter ablation (CA) is an important treatment option for children who have failed medical treatment of VA or who suffer from a VA resulting in LV dysfunction [8]. Moreover, CA presents the possibility of complete elimination of the rhythm disorder. In children, the reported experience of catheter ablation of VA is limited, highlighting the scarcity of VA ablative therapy in this population [5,[9][10][11][12][13][14][15]. Besides, acute and long-term success rates are both suboptimal and variable between centers. In some studies, up to one third of children experience arrhythmia recurrence following their initial ablation [5,[9][10][11][12][13][14][15]. Failure of CA and high recurrence rates may be explained by the lack of specifically designed small curved catheters for these patients, the non-inducibility of the tachycardia at procedure baseline, and to inherent technical challenges of the ablation site-including unstable catheter-tissue contact and close proximity to regions at risk for complications.
Currently, various CA techniques are utilized in the adult population. In children, manual (MAN)-guided radiofrequency (RF) ablation is still the most frequently used technique for VA ablation [8]. In adults, remote magnetic navigation (RMN)-guided RF ablation of VT has shown to be superior to manual-guided RF ablation in patients without structural heart disease [16][17][18]. Moreover, various studies reported significant advantages of RMN-guided ablation of supraventricular tachyarrhythmias (SVT) in children and adults with congenital heart defect (CHD) [19][20][21][22]. At present, no study has systematically evaluated the use of RMN guidance in pediatric VA ablation. Thus, we present the firstin-human investigation of this technique from a single highvolume CA center. This study aims to evaluate and compare procedural data and long-term outcomes between RMN-and manual-guided VA ablation in children.

Study Design and Population
This single-center, retrospective study, investigated all consecutive CA procedures using RMN or manual-guided RF techniques in children (aged < 18 years) as treatment of documented VA (including PVC or VT) between the 1st of January 2008 until 31th of December 2020. We excluded patients in whom cross-over between CA techniques occurred. Outcomes were compared between two groups, based on the ablation technique used: conventional manual-guided RF ablation (MAN) or RMN-guided RF ablation (RMN). All patients scheduled for VA ablation were distributed from the waiting list based on availability to the RMN-equipped or the conventional EP laboratory. Accordingly, ablation was performed either using RMN or using conventional MAN. The procedures were performed over the entire study duration by the same senior electrophysiologist group with the assistance of fellows, trained for manual catheter navigation as well as for RMN. The attending physicians performed RMN and MAN procedures in equal distribution. The primary endpoint for PVC ablation was > 90% reduction in PVC burden in comparison to baseline during long-term follow-up as measured by Holter continuous rhythm observation. The primary endpoint for VT ablation was absence of recurrence of sustained VT during long-term follow-up. We also analyzed the following secondary endpoints: procedural parameters (including fluoroscopy dosages), acute procedure success, redo procedure rates, and complication rates. The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki. The local medical ethics committee determined this study was not subject to the Dutch Medical Research Involving Human Subjects Act (WMO). The need for individual consent was waived by the local medical ethical committee.

Data Collection
Baseline demographic and clinical characteristics were collected from the institutional electronic patient dossier. Procedural data were derived both from the electronic medical files, as well as from the electronic procedural log files recorded with the EP-workmate

Definitions
Total procedure time was defined as the time from first puncture until the removal of sheaths. Major complications were permanent second-or third-degree atrioventricular block, cardiac tamponade, hemorrhagic shock, stroke, and procedure-related death. Minor complications were access site complications, temporary bundle branch block or AV block, pericardial effusion not requiring intervention. We considered as access site complications: bleeding complications or local vascular wall damage which required surgical intervention or intervention by radiologist, prolonged hospitalization and/or Hb drop of > 1.8 mmol/L.

Procedural Protocol
All antiarrhythmic drugs were discontinued for > 5 halflives before the procedure, except amiodarone. Procedures were performed under general anesthesia as per standard approach. Occasionally procedures were performed only with local anesthetic, based on operator preference when there was lack of PVC during sedation and patient/parent agreement. Vascular access was attained with placement of sheaths and diagnostic catheters in left and/or right femoral vein and/or artery, with sheath sizes and catheter types varying based on operator preference. Left-sided targets were approached by the retrograde aortic route. Three-dimensional electro-anatomic mapping (EAM) was performed in all patients using the EnSite NavX

Ablation Target
In patients with PVCs, the ablation target was the site of the earliest activation during activation mapping and/or the site of identical pace mapping. Acute success was defined as complete suppression of PVCs in the operating theater and during continuous rhythm monitoring during in-hospital stay. Regarding VT, if not incessant, VT was induced by programmed electrical stimulation (PES) and activation or entrainment mapping was performed if VT was hemodynamically tolerable, to identify the mechanism and to locate site of origin and/ or critical isthmuses and exit sites. In patients with enhanced automaticity and triggered activity mechanisms, the site of the earliest activation during activation mapping and/or the site of identical pace mapping was the target of ablation. In patients with reentry mechanisms (including patients with fascicular or scar-related VT), the main target was the critical isthmus using conventional diagnostic criteria (i.e. mid-diastolic potentials). Another target was the exit site of the VT circuit identified during activation mapping or pace mapping. In patients with VT, acute success was defined as non-inducibility of any VT using PES at the end of procedure. Testing with isoprenaline at the end of procedure was performed based on operator's preference. A standard of 30 min waiting time was applied to all procedures.

Follow-Up
Patients were seen at our outpatient clinic at 2 months after the procedure and subsequently on annual check-ups. When patients experienced symptoms, they were seen more frequently as determined by the treating physician. Pre-procedural PVC burden (number of PVCs/total number of beats) was collected in all patients, and was used as the reference value. Long-term success was assessed by Holter rhythm monitoring performed 3-6 months after catheter ablation in all patients, except in those with an implanted device (2 patients with ICD, 1 patient with ILR). Holter rhythm monitoring was performed more frequently if patients experienced symptoms during follow-up. Regarding PVC, longterm success was defined as a reduction of at least 90% of the PVC burden compared to the pre-procedural assessment. Regarding patients diagnosed with VTs, long-term success was regarded when a patient had no recurrences of sustained VT recorded on either 12-lead ECG, Holter rhythm monitoring, ILR, pacemaker or ICD.

Statistical Analysis
Normality was assessed by the Kolmogorov-Smirnov test, or when appropriate, Shapiro-Wilk test. Mean and standard deviation (SD) were calculated for normally distributed continuous variables. Median, interquartile range (IQR) and ranges were computed for continuous variables with non-normal distribution. Descriptive statistics for categorical data were expressed in absolute numbers and percentages. Normal distributed continuous variables were analyzed using the Student's T-test. For continuous variables with non-normal distributions, the Mann-Whitney U test was used. For comparing frequencies, the Chi-square test was used, or, when appropriate, Fisher's exact test. A 2-sided P-value of < 0.05 was considered significant. Data were analyzed using SPSS 26.0 (SPSS Inc., Chicago, IL, USA).

Results
In total, 33 VT and/or PVC ablation procedures were performed within the mentioned time frame. A cross-over between techniques occurred in 3 procedures, which were excluded (in two cases switch from MAN to cryoablation; in one case switch from RMN to MAN). Data from the remaining 30 procedures, performed in 22 patients were analyzed. These were 22 (73%) first procedures and 8 (27%) redo procedures. With respect to the first procedures, 10 patients (46%) were treated with RMN, whereas 12 (55%) were treated with the MAN technique. Regarding the redo procedures, 4 (50%) were performed with RMN and 4 (50%) with MAN (Fig. 1).

Baseline Demographic and Clinical Data
Baseline demographic and clinical data are presented in Table 1. Patients had a median age of 15 (IQR 14-17; range 1-17) years, with a mean weight of 57 ± 20 (range 16-95) kilograms. A minority was female (36%). Fifteen patients (68%) had no structural heart disease, whereas 3 patients (14%) had a dilated cardiomyopathy (DCM) and 4 patients (18%) had a CHD. In the patients with CHD the main defects were: (1) restrictive ventricular septal defect (VSD) (uncorrected), (2) mild native Ebstein's anomaly (uncorrected) (3) double outlet right ventricle (DORV) with transposition of the great arteries (TGA), ASD II, VSD and valvular and supravalvular pulmonalis stenosis, for which initially a Blalock Taussig shunt and later a Rastelli operation with a pulmonalis homograft was performed (4) TGA and VSD for which arterial switch operation and VSD closure was performed. Most patients had a normal left ventricular (LV) ejection fraction (EF) and right ventricular (RV) EF on TTE (77% and 96%, respectively), with normal LV and RV dimensions (82% and 96%, respectively). CHD was more frequently present in MAN compared to RMN (33% versus 0%, P = 0.044).

Procedural Data
In all RMN patients, PVC/VT was inducible at procedure baseline and subsequently activation mapping performed. In MAN the inducibility at baseline was 83%, which was comparable between groups (P = 0.18). More fascicular VT's were treated with RMN compared to MAN (50% versus 8%, respectively, P = 0.029). Outflow tract PVC/VT's were less frequently treated with RMN compared to MAN (30% versus 83%, respectively, P = 0.003). Most outflow tract targets were located in the RVOT [RVOT 11 (92%), LVOT 1 (8%), Aortic Cusp 1 (8%)]. In all patients with fascicular VT, the posterior fascicle was ablated (6 out of 6 (100%). Other LV/ RV targets of VA were found in 3 patients (14%), which was equally distributed between groups (P = 0.19). These included: (1) RV free wall anterior just below tricuspid valve, (2) RV free wall antero-lateral just below tricuspid valve and (3) RV septal infero-posterior involving the Purkinje network. The distribution of targets and treatment modalities is presented in Fig. 2. Of the patients with CHD, two had PVC's originating from the RVOT and two had a fascicular VT. In this cohort, no patient with structural heart disease had scar-related VT.

Long-term Outcome
We observed significantly fewer recurrences of VA in patients treated with RMN, compared to MAN (20% versus 67%, respectively, P = 0.029) at a mean follow-up time of 5.2 ± 3.0 years (Table 3 and Fig. 2). Follow-up time was comparable between groups (RMN: 4.6 ± 3.4 years versus MAN: 5.8 ± 2.5 years, P = 0.20). Two patients had a followup duration < 1 year because of transferral to another hospital (one RMN, one MAN). The redo procedure rate was higher in MAN group when compared to RMN, albeit not significant (RMN: 20% versus MAN: 58%, P = 0.070). Of the nine patients who underwent a redo procedure, one was performed in another center and another had no inducibility of any arrhythmia during the repeat procedure (i.e. no ablation was performed). The remaining 7 patients underwent 8 redo procedures in our center (Fig. 1). During all redo procedures the same target was ablated as during the first procedure, except for one patient where during the first procedure only the RVOT was treated and in the redo procedure both the RVOT and LVOT were ablated. In total, 20 patients (91%) were free of PVC/VT recurrence following their final ablation procedure.

Adverse Events
We observed no major complications and one minor complication in a patient treated with RMN who had temporary AV block, that resolved completely after the procedure (RMN 1 (10%) versus MAN 0 (0%), P = 0.26). One patient from the MAN group died 5 year after the ablation following an outof-hospital cardiac arrest for which resuscitation was performed. This patient had a double outlet right ventricle and had no ICD implanted. The cause of the circulatory arrest was unknown. The patient had no recurrence of sustained VT during regular annular check-ups.

Discussion
This is the first study to describe the use of RMN-guided RF ablation for pediatric PVC and VT ablation in a unique single-center population. The main finding of this study is that RMN is a feasible ablation technique for these arrhythmias in children and has improved long-term efficacy when compared to manual RF ablation.

Efficacy
Significantly fewer recurrences were observed in patients treated with RMN compared to MAN (20% versus 67%) at a mean follow-up of more than 5 years. The better outcome of patients treated with RMN can be attributed to some of the technical advantages of its design [23]. RMN catheters are not limited by fixed curves, have a greater flexibility and make more uniform contact, all of which contribute to improved lesion formation [23]. Magnetic-guided ablation by itself aids to achieve more adequate lesion formation by enhanced catheter stability and consequently improved contact with the myocardial wall [24]. This is of critical importance in cardiac regions with greater wall motion excursion such as the ventricle. A magnetic catheter also appears to produce less catheter-induced-ectopy, which is particularly important in PVC ablation when a mechanical PVC could cause the operator to ablate the wrong target [25]. The RMN-guided catheter's position can be stored and reapplied, which presents the ability to return precisely to critical locations to either assess delivery impact or deliver additional therapy. RMN facilitates titration of CF between the catheter and the myocardial tissue [23,26]. Therefore, RMN avoids excessive catheter indentations on cardiac wall that sometimes are unintentionally applied during manual manipulation of conventional catheters, which may eventually be responsible for cardiac perforation and tamponade [26,27]. These technical characteristics of RMN-guided catheter ablation are extremely beneficial in a small anatomy and, in addition, in treatment of targets at locations with marked wall excursions such as the ventricle. At present, ablative therapy remains reserved for highly symptomatic children who have failed medical treatment and/or established LV dysfunction [8]. The current study illustrated that RMN-guided CA procedures in this population are highly effective and safe, resulting in complete elimination of the rhythm disorder.

Fascicular VT Versus Outflow Tract VT
Significantly more fascicular VT were treated in the RMN group than in the manual group (50.0% versus 8.3%). This might have biased the outcomes, however, it is unlikely that the observed differences in outcomes-including fluoroscopic times and recurrence rates-are a result of this. Previously, Wu et al. showed that acute and long-term outcome did not differ between manual ablation of fascicular and nonfascicular VT in pediatric patients [28]. Similarly, Collins et al. reported no difference in initial success-with and without an intention to treat analysis -and recurrence rates between left-sided fascicular and nonfascicular VT ablation in pediatrics [5]. In addition, inclusion of more outflow tract VT in RMN group may even accentuate the improved performance of RMN-guided ablation, as its substrate may particularly benefit from the extra stability and flexibility provided by RMN, as shown in adults by Kawamura et al. [29].

Fluoroscopy Exposure
Besides improvement in clinical outcomes, advances in catheter ablation should strive to reduce radiation exposure, especially in pediatrics, as its effects are substantial for them. Compared to adults, children are ten times more vulnerable to the induction of cancer by external radiation exposure [30]. In our study, both techniques had low fluoroscopy dosages, but the lowest values were observed in RMN. This significant improvement in fluoroscopy exposure can be attributed to several factors. We hypothesize that the enhanced stability and flexibility enables faster access to the ablation site. Moreover, improved catheter stability causes less concern for catheter dislodgement resulting in less fluoroscopic confirmation of tip location. In addition, the atraumatic design of the catheter may result in more physician comfort maneuvring without continuous fluoroscopy. Collins et al. observed in an international multicentre study, including 152 pediatric patients, similar fluoroscopy times between ablation of fascicular and nonfascicular left VT (24 versus 28 min), comparable to the fluoroscopy times seen in patients treated with MAN ablation in this study [5]. Hence, the observed difference in our study is most likely a consequence of the ablation method, and to a lesser extent of the ablation indication. Nowadays, the utilization of 3D electroanatomic mapping systems and intracardiac echocardiography (ICE) systems allows for ablation procedures with limited or even without any fluoroscopy. Several studies observed that fluoroless ablation can be safely used in pediatric patients [31][32][33], also with respect to left-sided targets. Given the retrospective nature and inclusion period of our cohort, fluoroless ablation was not attempted in the current study cohort. However, in our opinion it is the current most favorable approach, especially when ablating the young patient.

Limitations
Due to the retrospective design of the study, its results are subjected to typical bias and limitation of retrospective research. Given the scarcity of VA ablative therapy during childhood, we had to search for a balance between inclusion period and numbers. In addition, this emphasizes the rarity of CA for ventricular rhythm disorders in children. The study population consisted of 7 patients with native structural heart disease (32%). However, as none had a scar-related VT, its impact on ablation technique outcomes is expected to be minimal. Despite these limitations, we believe this study presents an important first comparison of CA techniques in this particular population. Further prospective or randomized studies with larger and more homogenous groups, such as the OSCAPED registry, are required to confirm the observed outcomes, though difficult given the uncommonness of VA in children.
In conclusion, RMN is an effective and safe catheter ablation technique for the elimination of pediatric PVC and VT, resulting in significantly lower recurrence rates when compared to manual ablation, in addition to a low fluoroscopy exposure.

Conflict of interest
The authors declare that they have no conflict of interest.
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