Transesophageal Electrophysiological Study in Children Under 12 Years of Age with Asymptomatic Wolff–Parkinson–White Syndrome
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsThis retrospective study evaluated transesophageal electrophysiological study (TE-EPS) for risk stratification in asymptomatic children with Wolff–Parkinson–White (WPW) syndrome, focusing on age-related differences using a 12-year sedation threshold. Forty-one children (1–18 years) underwent TE-EPS; those <12 years were studied under conscious sedation, whereas older children were not. Three established high-risk parameters were assessed: accessory pathway effective refractory period (APERP), minimal cycle length with 1:1 antegrade conduction, and shortest pre-excited RR interval during induced atrial fibrillation (AF). While APERP and antegrade conduction did not differ between age groups, inducible AF and high-risk pathways were significantly more frequent in children >12 years, resulting in catheter ablation in 11 older children versus one younger child. Although strong correlations existed among risk markers, Bland–Altman analysis revealed notable discordance, supporting a multiparametric approach. These findings suggest TE-EPS is a safe and effective risk-stratification tool in asymptomatic children, particularly those under 12 years, in whom high-risk pathways are uncommon and invasive ablation may often be avoided.
1. The choice of 12 years as a cutoff is pragmatic but insufficiently justified physiologically. The manuscript would benefit from a clearer explanation linking this threshold to atrial size, autonomic tone, sedation requirements, or prior guideline recommendations.
2. Sedation was used exclusively in children under 12 and may significantly affect atrial vulnerability and inducibility of AF. This represents a major confounder and should be emphasized earlier (Methods and Results), not only in the limitations.
3. Given the small sample size—particularly in the <12-year subgroup—the manuscript should include a brief statement on statistical power limitations, especially for negative findings (e.g., lack of APERP differences).
4. The study focuses on electrophysiological risk markers but lacks long-term outcomes such as arrhythmic events, syncope, or sudden cardiac death. Even limited follow-up data would substantially enhance clinical relevance.
5. The conclusion appropriately favors TE-EPS in younger children but should more clearly state that findings are hypothesis-generating and not sufficient to change guideline-level recommendations.
Author Response
We thank both reviewers for their thoughtful and constructive comments. We appreciate the time and effort they devoted to evaluating our manuscript, and we believe their feedback has helped improve its quality. The comments from Reviewer 1 and our corresponding responses are presented below. Revisions in the manuscript are indicated in red.
Reviewer 1:
This retrospective study evaluated transesophageal electrophysiological study (TE-EPS) for risk stratification in asymptomatic children with Wolff–Parkinson–White (WPW) syndrome, focusing on age-related differences using a 12-year sedation threshold. Forty-one children (1–18 years) underwent TE-EPS; those <12 years were studied under conscious sedation, whereas older children were not. Three established high-risk parameters were assessed: accessory pathway effective refractory period (APERP), minimal cycle length with 1:1 antegrade conduction, and shortest pre-excited RR interval during induced atrial fibrillation (AF). While APERP and antegrade conduction did not differ between age groups, inducible AF and high-risk pathways were significantly more frequent in children >12 years, resulting in catheter ablation in 11 older children versus one younger child. Although strong correlations existed among risk markers, Bland–Altman analysis revealed notable discordance, supporting a multiparametric approach. These findings suggest TE-EPS is a safe and effective risk-stratification tool in asymptomatic children, particularly those under 12 years, in whom high-risk pathways are uncommon and invasive ablation may often be avoided.
Comment 1: The choice of 12 years as a cutoff is pragmatic but insufficiently justified physiologically. The manuscript would benefit from a clearer explanation linking this threshold to atrial size, autonomic tone, sedation requirements, or prior guideline recommendations.
Response 1: The reviewer is correct that the choice of 12 years represents a pragmatic threshold. This cutoff was selected based on prior electrophysiological studies, including those by Brembilla-Perot et al., in which 12 years is commonly used as the age distinguishing sedation versus non-sedation during electrophysiological study. In addition to this practical consideration, younger age is associated with physiological factors relevant to atrial fibrillation inducibility, including smaller atrial size, longer atrial effective refractory periods, and a lower likelihood of sustaining atrial fibrillation. These observations are consistent with the “critical mass” theory, which proposes that a minimum atrial mass is required to maintain fibrillatory activity and has been demonstrated in experimental and computational models. While autonomic tone differs in children compared with adults, atrial size appears to play a more prominent role in atrial fibrillation inducibility. In addition, developmental changes in accessory pathways further support the age-based stratification. Morphopathological studies have demonstrated that accessory atrioventricular connections are more prevalent during fetal life and early infancy and decrease in number with maturation of the atrioventricular fibrous rings. When accessory pathways persist beyond infancy, those with longer effective refractory periods appear more likely to lose anterograde conduction with increasing age. We have revised the manuscript to better articulate both the pragmatic and physiological rationale for the 12-year cutoff.
References:
- Garrey W. The nature of fibrillary contraction of the heart: its relation to tissue mass and form. American Journal of Physiology. 1914;33:397–414;
- Zou R, Kneller J, Leon LJ, Nattel S. Substrate size as a determinant of fibrillatory activity maintenance in a mathematical model of canine atrium. Am J Physiol Heart Circ Physiol. 2005 Sep;289(3):H1002–12.; Farges JP, Faucon G, Lievre M, Ollagnier M. Relationship between atrial and ventricular rates of fibrillation and cardiac contractile tissue effective refractory periods in the dog. Br J Pharmacol. 1978 Aug;63(4):587–91; Vaidya D, Morley GE, Samie FH, Jalife J. Reentry and fibrillation in the mouse heart. A challenge to the critical mass hypothesis. Circ Res. 1999 Jul 23;85(2):174–81.
- Bufo MR, Guidotti M, De Faria C, Mofid Y, Bonnet-Brilhault F, Wardak C, Aguillon-Hernandez N. Autonomic tone in children and adults: Pupillary, electrodermal and cardiac activity at rest. Int J Psychophysiol. 2022 Oct;180:68-78.
Comment 2: Sedation was used exclusively in children under 12 and may significantly affect atrial vulnerability and inducibility of AF. This represents a major confounder and should be emphasized earlier (Methods and Results), not only in the limitations.
Response 2: Thank you for this observation. We have revised the manuscript to more prominently address the use of sedation in children under 12 years of age. Details regarding sedation are now included in the Methods section, and its potential association with atrial vulnerability and atrial fibrillation inducibility is reported in the Results section. The Discussion has been expanded to emphasize Propofol use as a potential confounder and to discuss its implications for interpretation of the findings.
Comment 3: Given the small sample size—particularly in the <12-year subgroup—the manuscript should include a brief statement on statistical power limitations, especially for negative findings (e.g., lack of APERP differences).
Response 3: Due to the limited sample size of our study: 41 children (15 vs 26 per group), it may offer sufficient power only for moderate to large effects but not enough power to identify minor differences between the two groups. Potentially clinically significant differences cannot be ruled out even if we found no differences between the two groups in terms of APERP, 1:1 conduction over the accessory pathway or shortest preexcited RR interval during atrial fibrillation. Therefore, the lack of statistically significant differences should be viewed cautiously, and our results should be regarded as hypothesis-generating until larger, sufficiently powered studies validate them.
Comment 4: The study focuses on electrophysiological risk markers but lacks long-term outcomes such as arrhythmic events, syncope, or sudden cardiac death. Even limited follow-up data would substantially enhance clinical relevance.
Response 4: Although long-term clinical outcomes were not a primary endpoint of the study, follow-up data were available for all patients. During follow-up, no patient experienced syncope or sudden cardiac death. Eleven children subsequently underwent intracardiac electrophysiological study with catheter ablation of the accessory pathway, with an immediate procedural success rate of 100%. Two patients experienced recurrence at three- and ten-month follow-up, respectively, and required repeat ablation. These follow-up data have now been added to the Results section and are discussed to provide additional clinical context.
Comment 5: The conclusion appropriately favors TE-EPS in younger children but should more clearly state that findings are hypothesis-generating and not sufficient to change guideline-level recommendations.
Response 5: We have revised the Conclusion to more explicitly state that the findings are hypothesis-generating. While the results support the use of transesophageal electrophysiological evaluation in younger, asymptomatic children following identification of a Wolff–Parkinson–White pattern on electrocardiography, they are not sufficient to justify changes to current guideline-level recommendations.
Reviewer 2 Report
Comments and Suggestions for AuthorsThe manuscript entitled Transesophageal electrophysiological study in children under 12 years with asymptomatic Wolff-Parkinson-White syndrome is an original study. This retrospective study assessed the risk of sudden cardiac death in children with asymptomatic Wolff-Parkinson-White syndrome using transesophageal study, considering a threshold age of 12 years for sedation. The risk of sudden cardiac death was evaluated by three electrophysiologic parameters: 1) accessory pathway effective refractory period (APERP), 2) the minimal cycle length demonstrating 1:1 conduction through the accessory pathway and 3) the shortest RR interval between two consecutive preexcited beats during atrial fibrillation.
The authors concluded that these patients had accessory pathways with reduced risk, and none of the children under 12 years necessitated catheter ablation.
This is an interesting, even small, study. The manuscript is well written. However, I have some issues to discuss.
Thak you for taking into consideration the influence of sedation on the electrophysiologic study.
Major revision
Informed consent was obtained only prior to the transesophageal study? Please detail.
Please add the number of the Ethics Committee's opinion from the 2 units where the patients were included.
What do you mean by stress test in studied population? Please clarify.
What were the reasons why these children ended up seeing an arrhythmologist? It is interesting to know, given their age and lack of symptoms. Please add these reasons in the manuscript.
The authors stated : ‘’ The patients underwent a protocol of single extrastimuli pacing as well as rapid atrial pacing in the baseline state.’’ Are there differences of the protocol used for electrophysiologic study for children comparing with the adults? Please detail.
The authors stated that: ‘’ none of the children under 12 years necessitated catheter ablation.’’ Unfortunately, in table 1 was noted 1 patient. Please verify data accuracy.
What are the current recommendations for children related to the transesophageal electrophysiological study? Please include them in discussion.
Have you tried pharmacological induction of atrial fibrillation? Or just pacing?
It would be interesting to add the location of the accessory pathways in these patients.
Minor revision
There are some minor errors of editing in English language. (for example: effectife on page 2 line 81).
In table 1 please delete n= from the first two raw and, also, in the raw 8 and 9. Please verify all tables.
On page 4 line 157 there is noted: ‘’ Figure 1. This is a figure. Schemes follow the same formatting.’’ Please verify what is it about because the same phrase is under the Figure 1 (a,b,c).
Author Response
We express our gratitude to both reviewers for their insightful remarks. We appreciate the time and effort the reviewers dedicated to evaluating our work. Their critique enhanced the quality of our manuscript.
The comments from Reviewer 2 and our subsequent responses are presented below. Changes are marked inside the manuscript with red color.
Reviewer 2:
The manuscript entitled Transesophageal electrophysiological study in children under 12 years with asymptomatic Wolff-Parkinson-White syndrome is an original study. This retrospective study assessed the risk of sudden cardiac death in children with asymptomatic Wolff-Parkinson-White syndrome using transesophageal study, considering a threshold age of 12 years for sedation. The risk of sudden cardiac death was evaluated by three electrophysiologic parameters: 1) accessory pathway effective refractory period (APERP), 2) the minimal cycle length demonstrating 1:1 conduction through the accessory pathway and 3) the shortest RR interval between two consecutive preexcited beats during atrial fibrillation. The authors concluded that these patients had accessory pathways with reduced risk, and none of the children under 12 years necessitated catheter ablation. This is an interesting, even small, study. The manuscript is well written. However, I have some issues to discuss.
Comment 1: Thank you for taking into consideration the influence of sedation on the electrophysiologic study.
Response 1: Thank you. We completed the Discussion section with a paragraph addressing the impact of midazolam and propofol on the electrophysiologic study.
Comment 2: Informed consent was obtained only prior to the transesophageal study? Please detail.
Response 2: Yes. Informed consent was obtained only before the transesophageal examination. The study received approval from the Institutional Review Boards of The Monza Hospital (No 5/ 15.01.2025 ) and Napoca Clinic (No 4/12.01.2025). Due to its retrospective observational design, the IRB concluded that all data were adequately protected against unauthorized access or disclosures, and individual informed consent was deemed unnecessary.
Comment 3: What do you mean by stress test in studied population? Please clarify.
Response 3: Children over 6 years of age underwent a treadmill stress test to determine the maximum heart rate and assess atrioventricular conduction. We included children without clear, abrupt loss of preexcitation. For individuals under 6, the Holter ECG was the sole non-invasive test utilized before transesophageal examination.
Comment 4: What were the reasons why these children ended up seeing an arrhythmologist? It is interesting to know, given their age and lack of symptoms. Please add these reasons in the manuscript.
Response 4: In our center, all children diagnosed with WPW syndrome by a pediatric cardiologist are referred for an arrhythmology consultation. The majority of children were referred to the arrhythmologist due to their participation in sports, necessitating the cardiologist'approval to continue engaging in high-intensity physical activity. All of them were asymptomatic. A small number of children were diagnosed with asymptomatic WPW upon their presentation to the Emergency Department due to upper respiratory tract infection. The 1-year-old boy underwent an electrophysiological testing because his brother died at the age of 8 month with a sudden infant death syndrome; he had never undergone a cardiological examination.
Comment 5: The authors stated : ‘’ The patients underwent a protocol of single extrastimuli pacing as well as rapid atrial pacing in the baseline state.’’ Are there differences of the protocol used for electrophysiologic study for children comparing with the adults? Please detail.
Response 5: The pacing protocol is similar in children and adults, using one, two, or three extrabeats in the atrium to generate arrhythmias, depending upon the center and the operator's preference. However, children typically exhibit higher resting rates, surpassing those of adults, with increased atrioventricular conduction resulting in shorter basal cycle lengths used in children, with shorter coupling intervals of the atrial extrastimulus compared to adults.
Comment 6: The authors stated that: ‘’ none of the children under 12 years necessitated catheter ablation.’’ Unfortunately, in table 1 was noted 1 patient. Please verify data accuracy.
Response 6: Table 1 indicates one patient with a high-risk accessory pathway however, ablation was delayed by the parents.
Comment 7: What are the current recommendations for children related to the transesophageal electrophysiological study? Please include them in discussion.
Response 7: The PACES/HRS Expert consensus on the management of the asymptomatic young patient with a Wolff-Parkinson-White electrocardiographic pattern recommend utilization of transesophageal or intracardiac EP study to assess the risk of the accessory pathway in individuals 8 to 21 years whose noninvasive testing did not demonstrate clear and abrupt loss of preexcitation (Class 2A, LOE B/C). SPERRI < 250 ms in atrial fibrillation are at increased risk for sudden cardiac death and catheter ablation is reasonable (Class 2A, LOE B/C.). SPERRI > 250 ms in atrial fibrillation are at lower risk of sudden cardiac death and it is reasonable to defer catheter ablation (Class 2A, LOE C.).
Comment 8: Have you tried pharmacological induction of atrial fibrillation? Or just pacing?
Response 8: We did not attempt pharmacological induction of atrial fibrillation. Neither with adrenaline nor with isoprenaline. We used only transesophageal atrial pacing.
Comment 9: It would be interesting to add the location of the accessory pathways in these patients.
Response 9: The localization of the accessory pathway assessed in maximal preexcitation was left lateral in 10 cases, right lateral in 2 cases, posteroseptal (left or right) in 20 cases and anteroseptal in 9 cases.
Minor Revisions
Comment 10: There are some minor errors of editing in English language. (for example: effectife on page 2 line 81).
Response 10: Thank you. We corrected the error
Comment 11: In table 1 please delete n= from the first two raw and, also, in the raw 8 and 9. Please verify all tables.
Response 11: Thank you. We appreciate your attention. We corrected the error
Comment 12: On page 4 line 157 there is noted: ‘’ Figure 1. This is a figure. Schemes follow the same formatting.’’ Please verify what is it about because the same phrase is under the Figure 1 (a,b,c).
Response 12: Thank you. We have deleted both phrases.
Round 2
Reviewer 2 Report
Comments and Suggestions for AuthorsThank you for responding to my comments.
