Introduction
Ventricular pre-excitation carries a low but lifetime risk of sudden cardiac death (up to 2.8 per 1000 patient-years), which is apparently higher in symptomatic patients. However, patients with ventricular pre-excitation sometimes remain asymptomatic during childhood and may become symptomatic during adolescence; moreover, sudden cardiac death can be the first manifestation of the disease.Reference Fitzsimmons, McWhirter, Peterson and Kruyer1–Reference Obeyesekere, Leong-Sit and Massel7
In this regard, management of asymptomatic children with pre-excitation remains debated. An electrophysiological study can be used for the risk stratification of these patients, especially when sports eligibility for competitive athletes is required.Reference Delise, Mos and Sciarra8–Reference Pelliccia, Sharma and Gati10 Indeed, physical activity on a competitive level has been associated with increased risk of arrhythmic events in these patients.Reference Książczyk, Pietrzak and Werner11
Moreover, the electrophysiological properties of accessory pathways may vary during growth. However, only a few studies have analysed the changes in accessory pathway properties over time,Reference Béatrice, Sellal and Olivier12–Reference Vignati, Balla, Mauri, Lunati and Figini14 but they included both children and adults or performed transcatheter ablation between the two electrophysiological studies.
Therefore, the aim of this study was to assess changes in electrophysiological characteristics of accessory pathways and atrial vulnerability in paediatric patients with manifest ventricular pre-excitation who were referred for sports eligibility.
Methods
Study design and population
This was a retrospective, single-centre, observational study and complied with the Declaration of Helsinki.
Written informed consent was obtained from the parents of all the patients prior to the procedure.
The study enrolled all paediatric athletes (<18 years) with ventricular pre-excitation (32 males, 12 females) who were repeatedly evaluated through an electrophysiological study for sports eligibility between January 2011 and July 2022.
The definition adopted for “athlete” was: “an individual of young or adult age, either amateur or professional, who is engaged in regular exercise training and participates in official sports competition,” according to the European Society of Cardiology indications.Reference Pelliccia, Sharma and Gati10
In all patients, transcatheter ablation was not performed between the two evaluations due to parents’ choice, use of antiarrhythmic drugs, or accessory pathway’s locations at risk of procedural complications (i.e. anterior septal accessory pathways or probable epicardial location).
Transesophageal or endocavitary electrophysiological study evaluation was performed at two different life periods (T0 and T1) within a minimal interval of 2 years.
All antiarrhythmic drugs were discontinued for at least five half-lives before the procedure to ensure complete pharmacological washout.
The electrophysiological and clinical data were collected and compared.
Transesophageal electrophysiological study
A transesophageal electrophysiological study was performed as a screening test according to Italian guidelines for sports participation.Reference Delise, Mos and Sciarra8
Children were considered non-collaborative or collaborative based on their age, capability, and/or willingness to perform exercise testing.
In non-collaborative patients, transesophageal electrophysiological study was performed under deep sedation (60% O2, 39.8% N2O 0.8% sevoflurane). In collaborative patients, local anaesthesia with 1% nasal and oral lidocaine spray was established prior to the insertion of the oesophageal catheter. A 7-French tetrapolar oesophageal catheter (FIAB Esoflex 4S; Vicchio-Florence, Italy) was advanced through the nose into the oesophagus at an appropriate depth, where the maximal amplitude of the bipolar atrial potential was recorded. Cardiac stimulation was performed with a programmable stimulator (FIAB 8817) using a pulse width of 10 ms and a stimulus current amplitude that was slightly in excess, resulting in consistent atrial capture (15–20 V).
At rest, stimulation was performed at a fixed cycle length (600 or 450 ms, according to the spontaneous sinus rate) with one, two, or three extra stimuli. Bursts of decreasing cycle length (600–150 ms by reducing 50 ms every 5 s) were delivered and repeated thrice.
The same stimulation protocol was repeated under intravenous isoproterenol infusion (0.02-0.08 mg/kg/min) or
Accessory pathway effective refractory period was defined as the longest A1–A2 interval that failed to conduct through the accessory pathway and conducted through the atrial-ventricular node. The 1:1 conduction over the accessory pathway was measured during incremental atrial pacing.
The shortest pre-excited R-R interval during atrial fibrillation was measured in milliseconds during induced atrial fibrillation.
Accessory pathways were considered “high-risk” in case of shortest pre-excited R-R interval ≤ 250 ms during incremental atrial pacing of induced atrial fibrillation and/or an accessory pathway effective refractory period ≤ 250 ms obtained by programmed atrial stimulation protocol, performed at baseline or during adrenergic stress.Reference Brugada, Katritsis and Arbelo15–Reference Moore, Kannankeril and Fish17
The duration and cycle length of the induced atrioventricular re-entry tachycardia and atrial fibrillation were recorded in seconds and defined as non-sustained when they lasted < 30 s. In cases of sustained arrhythmia associated with hemodynamic intolerance, sinus rhythm was restored by burst pacing or external electrical cardioversion.
In patients without inducible atrioventricular re-entry tachycardia/atrial fibrillation and/or with non-high-risk resting electrophysiological parameters, the pacing protocol was repeated during exercise testing with a cycle ergometer or under isoproterenol infusion (0.04–0.08 mcg/kg/min), in order to reach at least a 50% increase of heart rate and/or a target heart rate of 140–150 bpm.
The same stimulation protocol was applied at T0 and T1.
Intracardiac electrophysiological study
Intracardiac electrophysiological study was performed only in young athletes for whom a transcatheter ablation was initially planned and in agreement with patients’ parents.
The procedure was performed under general anaesthesia with endotracheal intubation, induced with sevoflurane or propofol, and maintained with sevoflurane. A thermal mattress was used to maintain a normal body temperature.
Surface electrocardiogram leads and endocardial potentials were recorded and stored on a multichannel recorder (Bard Electrophysiology, Billerica, MA, USA). The bipolar bandwidth filter was set in the range of 30–300 Hz.
The same electrophysiological parameters analysed in the transesophageal electrophysiological study were also assessed during the electrophysiological study.
Statistical analysis
Descriptive statistics were reported as mean ± standard deviation or median and interquartile range for continuous variables, as appropriate; the results are presented as frequencies for categorical variables. A preliminary analysis and subsequently the Kolmogorov-Smirnov test were performed to test the normality of the continuous data. Although a model assumption of normality was documented in some situations, we considered the non-normality of the distribution of the studied variables owing to the small sample size, and nonparametric models were used. For statistical analysis, continuous variables were compared using the Mann–Whitney test. Categorical variables were analysed using a contingency table with a Chi-squared test. Differences were considered statistically significant at a P-value < 0.05. Data analysis was performed using MedCalc Statistical Software version 15.8 (MedCalc Software bvba, Ostend, Belgium; https://www.medcalc.org; 2015).
Results
Patients characteristics
There were 44 children with manifest ventricular pre-excitation, who were evaluated for sports eligibility [32 (73%) males, mean age 10 ± 2.42 years at T0 and 14.11 ± 2.11 years at T1].
The second electrophysiological evaluation (T1) was performed at a minimum interval of two years (mean interval 4.11 ± 2.27 years) in all patients.
Electrophysiological data
Transesophageal electrophysiological study was performed on 40 patients (90.9%) at T0 and 41 (93.2%) at T1. The remaining patients underwent intracardiac electrophysiological study.
No procedure-related complications occurred.
The stimulation protocol was performed during adrenergic stress (isoproterenol infusion or exercise stress testing) in 90.9% and 97.7% of patients at T0 and T1, respectively.
Under the baseline condition, a significant reduction in the accessory pathway effective refractory period and 1:1 conduction over the accessory pathway was observed between T0 and T1 (see Table 1). However, no significant differences in these parameters were observed during adrenergic stress (see Table 2).
Table 1. Electrophysiological study at rest
P value < 0.05 is considered as statistically significant.
AF = Atrial fibrillation; AP = accessory pathway; APERP = Accessory pathway effective refractory period; ARVT = atrioventricular re-entry tachycardia; AV = atrioventricular; ERP = effective refractory period; EPS = electrophysiological study; SPERRI = shortest pre-excited R-R interval; WCL = Wenckebach cycle length.
Table 2. Electrophysiological study during adrenergic stress
P value < 0.05 is considered as statistically significant.
AF = Atrial fibrillation; AP = accessory pathway; APERP = Accessory pathway effective refractory period; ARVT = atrioventricular re-entry tachycardia; AV = atrioventricular; ERP = effective refractory period; EPS = electrophysiological study; SPERRI = shortest pre-excited R-R interval; WCL = Wenckebach cycle length.
Both atrioventricular re-entry tachycardia and atrial fibrillation were inducible in a not negligible proportion of patients (see Tables 1 and 2). Atrioventricular re-entry tachycardia inducibility was not significantly different between T0 and T1, although an upward trend was observed (see Tables 1 and 2).
Atrial fibrillation induction was different at rest but not during adrenergic stress, whereas the shortest pre-excited R-R interval during adrenergic stress decreased significantly (see Tables 1 and 2).
The electrophysiological study showed “high-risk” properties in thirty-five children and “low-risk” properties in three patients both at T0 and T1. Six patients (13.6%) changed the risk profile of accessory pathway: two “high-risk” patients at T0 became “low-risk” and four “low-risk” patients became “high-risk” (see Table 3).
Table 3. Electrophysiological characteristic of patients changing risk category between the evaluations (T0 and T1)
NA = in case of intermittent VP, when AP conduction is not visible at the time of EPS or AP refractory period > CL of stimulation.
AP = accessory pathway; EPS = intracavitary electrophysiological study; ERP = effective refractory period; SCD = sudden cardiac death; SPERRI; shortest pre-excited R-R interval; TEE = transoesophageal study.
During the study period, accessory pathway anterograde conduction was preserved in all patients, but one child with a constant ventricular pre-excitation on ECG developed an intermittent form.
None of our patients presented with documented life-threatening or poorly tolerated arrhythmic events (atrial fibrillation or ventricular tachycardia/ventricular fibrillation).
Discussion
The role of electrophysiological study to evaluate the pre-excitation syndrome-related risks of adverse events has been proven in previous studies.Reference Munger, Packer and Hammill4,Reference Di Mambro, Russo and Righi6,Reference Obeyesekere, Leong-Sit and Massel7,Reference Wever and Robles de Medina18,Reference Pappone, Vicedomini and Manguso19 In this regard, all the recent guidelines suggest performing an electrophysiological study on all young athletes with ventricular pre-excitation.Reference Delise, Mos and Sciarra8,Reference Pelliccia, Sharma and Gati10,Reference Brugada, Katritsis and Arbelo15
However, the evolution of electrophysiological properties of accessory pathway during life has been reported in a few papers.Reference Béatrice, Sellal and Olivier12–Reference Vignati, Balla, Mauri, Lunati and Figini14,Reference Brembilla-Perrot, Vincent, Olivier, Bozec, Girerd and Sellal20,Reference Fan, Peter, Gang and Mandel21
The Italian screening programme for sports eligibility requires a cardiovascular assessment to be performed every year and the electrophysiological study for risk stratification of ventricular pre-excitation can be repeated at the discretion of the sports physicians.Reference Delise, Mos and Sciarra8,Reference Di Mambro, Drago and Milioni9,Reference Sarto, Zorzi and Merlo22
Consequently, our study population affected by ventricular pre-excitation was repeatedly evaluated using the electrophysiological study to obtain sports eligibility, especially focusing on arrhythmic vulnerability and changes in accessory pathway anterograde conduction.
Our results showed that significant changes in electrophysiological data could occur during growth. Indeed, we observed a significant modification in the conduction properties of the accessory pathways.
Specifically, the accessory pathway effective refractory period and 1:1 conduction over the accessory pathway significantly decreased at rest, whereas shortest pre-excited R-R interval decreased during the adrenergic stress test.
Notably, in our study population, 13.6% of the patients had changes in accessory pathway properties, with a consequent switch between the risk categories. Furthermore, in the resting condition, atrioventricular re-entry tachycardia and atrial fibrillation showed an increasing trend of inducibility at T1.
Consequently, we believe that a repeated electrophysiological study during growth may improve the risk stratification for sudden cardiac death in young athletes with ventricular pre-excitation. Indeed, patients at “low-risk” may become at “high-risk” and vice versa, and tachycardia inducibility may vary with time according to different conduction properties of atrioventricular node and accessory pathways with the growth of patients and their hearts. Moreover, when a transoesophageal electrophysiological study can be performed, the risks connected to the electrophysiological evaluation are minimal.
Differently from our study, Brembilla–Perrot,Reference Brembilla-Perrot, Vincent, Olivier, Bozec, Girerd and Sellal20 describing the follow-up (6.3 ± 4.8 years) of 47 children with ventricular pre-excitation (mean age 12.2 ± 4.3 at first evaluation), reported that there were no significant changes in clinical and electrophysiological study data. In this regard, we believe that these different findings could be due to the younger age of our patients at T0 (10.01 ± 2.42 years) with consequent different periods of the paediatric age analysed.
Interestingly, in the Brembilla–Perrot’s study, most children with spontaneous/inducible atrioventricular re-entry tachycardia at the time of initial electrophysiological study still had inducible tachycardia at the time of the second electrophysiological study. In this regard, Vignati and DragoReference Vignati, Balla, Mauri, Lunati and Figini14 reported that the tachycardia disappeared in approximately 50% of the patients during the first year of life and atrioventricular re-entry tachycardia very rarely disappears in patients who develop the tachycardia after 12 years of age.
Our data confirm that atrioventricular node effective refractory period increases with age,Reference DuBrow, Fisher and Amaty-Leon23 with different but not significant atrioventricular re-entry tachycardia inducibility. On the contrary, the accessory pathway effective refractory period decreased in contrast to the “impedance mismatch” theory (22–24), according to which the relatively small accessory pathway current can be easily blocked by the larger mass of the ventricular myocardium, which is expected to grow during the paediatric age.
Our data also revealed a larger number of “high-risk” patients than in the Brembilla–Perrot’s study, probably because our definition of “high risk” is in accordance with the latest European guidelines available and the Italian Recommendation for sport eligibility.Reference Delise, Mos and Sciarra8,Reference Brugada, Katritsis and Arbelo15
Notably, the accessory pathway anterograde conduction was preserved in all but one patient in our study population even if MilsteinReference Milstein, Sharma and Klein24 reported that a considerable number of asymptomatic patients can lose their capacity for anterograde conduction over the accessory pathway.
Lastly, none of our patients presented with a documented life threatening or poorly tolerated arrhythmic event (neither atrial fibrillation nor ventricular tachycardia/ventricular fibrillation), despite the high prevalence of so-called high-risk accessory pathways.
Future studies with a long-term follow-up are expected to establish whether our results can be confirmed in larger populations. In addition, our risk stratification protocol with a repeated electrophysiological study during growth could be compared to the present standard of care to investigate if it can improve outcomes in these patients.
Limitations
This was a retrospective single-centre study with a small number of patients; therefore, the results could be influenced by the population selection and characteristics.
The definition of athletes may vary in different countries and/or hospitals. In this paper, athletes were defined as reported in the most recent European Society of Cardiology guidelines.Reference Pelliccia, Sharma and Gati10
Lastly, it has been already described that measurements of refractoriness and conduction properties of accessory pathway can be not reproducible also during the same electrophysiological procedure.Reference Oliver and Brembilla-Perrot26
Conclusion
This study highlights the importance of repeating electrophysiological study (transesophageal or intracardiac electrophysiological study) in paediatric athletes with ventricular pre-excitation, because significant and clinically relevant changes in the conduction and refractoriness of accessory pathway can occur. This could influence risk stratification for sports eligibility and the correct indication and timing for accessory pathway ablation that is essential to avoid sudden cardiac death in young athletes potentially at risk. For this purpose, the use of isoproterenol infusion or exercise testing during the stimulation protocol further increases the sensitivity of electrophysiological testing and possibly its predicting value in athletes.
Data availability statement
The data that support the findings of this study are available on reasonable request from the corresponding author.
Acknowledgements
The authors would like to thank Dr Elisa Del Vecchio for her valuable collaboration in the editorial revision. Our centre is a health care provider of the European Reference Network GUARD-Heart.
Financial support
This work was supported by the Italian Ministry of Health with “Current Research funds” (202203_FBG_DRAGO).
Competing interests
None.
Ethical standard
The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national guidelines and with the Helsinki Declaration of 1975, as revised in 2008, and has been approved by the institutional committees of our Institution.
