Life-Threatening Event Risk in Children With Wolff-Parkinson-White Syndrome A Multicenter International Study ABSTRACT OBJECTIVES This study sought to characterize risk in children with Wolff-Parkinson-White (WPW) syndrome by comparing those who had experienced a life-threatening event (LTE) with a control population. BACKGROUND Children with WPW syndrome are at risk of sudden death. METHODS This retrospective multicenter pediatric study identified 912 subjects #21 years of age with WPW syndrome, using electrophysiology (EPS) studies. Case subjects had a history of LTE: sudden death, aborted sudden death, or atrial fibrillation (shortest pre-excited RR interval in atrial fibrillation [SPERRI] of #250 ms or with hemodynamic compromise); whereas subjects did not. We compared clinical and EPS data between cases and subjects. RESULTS Case subjects (n ¼ 96) were older and less likely than subjects (n ¼ 816) to have symptoms or documented tachycardia. Mean age at LTE was 14.1 3.9 years of age. The LTE was the sentinel symptom in 65%, consisting of rapidly conducted pre-excited atrial fibrillation (49%), aborted sudden death (45%), and sudden death (6%). Three risk components were considered at EPS: SPERRI, accessory pathway effective refractory period (APERP), and shortest paced cycle length with pre-excitation during atrial pacing (SPPCL), and all were shorter in cases than in control subjects. In multivariate analysis, risk factors for LTE included male sex, Ebstein malformation, rapid anterograde conduction (APERP, SPERRI, or SPPCL #250 ms), multiple pathways, and inducible atrial fibrillation. Of case subjects, 60 of 86 (69%) had $2 EPS risk stratification components performed; 22 of 60 (37%) did not have EPS-determined high-risk characteristics, and 15 of 60 (25%) had neither concerning pathway characteristics nor inducible atrioventricular reciprocating tachycardia. CONCLUSIONS Young patients may experience LTE from WPW syndrome without prior symptoms or markers of highrisk on EPS. (J Am Coll Cardiol EP 2017;-:-–-) © 2017 by the American College of Cardiology Foundation. From the aDivision of Cardiology, Department of Pediatrics, Primary Children’s Hospital, University of Utah, Salt Lake City, Utah; bDivision of Cardiology, Department of Pediatrics, Stollery Children’s Hospital, University of Alberta, Edmonton, Alberta, Canada; cDivision of Pediatric Cardiology, Department of Pediatrics, Cohen Children’s Medical Center of New York, Hofstra-Northwell School of Medicine, New Hyde Park, New York; dDepartment of Pediatrics, Division of Cardiology, Stead Family Children’s Hospital, University of Iowa, Iowa City, Iowa; eDivision of Cardiology, Department of Pediatrics, University of Michigan Children’s Hospital, University of Michigan, Ann Arbor, Michigan; fLabatt Family Heart Centre, Hospital for Sick Children, Toronto, Ontario, Canada; gDivision of Pediatric Cardiology, Department of Pediatrics, Lucile Packard Children’s Hospital, Stanford University, Palo Alto, California; hGreenlane Paediatric and Congenital Cardiac Service, Starship Children’s Hospital, University of Auckland, Auckland, New Zealand; iCardiology Division, Department of Pediatrics, Rady Children’s Hospital, University of California San Diego, San Diego, California; jDivision of Cardiology, Children’s Hospital Colorado, University of Colorado, Aurora, Colorado; kDivision of Pediatric Cardiology, Department of Pediatrics, Seattle Children’s Hospital, Seattle, Washington; lCardiocentro Pediatrico William Soler, Havana, Cuba; mDepartment of Paediatric Cardiology, University Hospital of Wales, Cardiff, Wales, United Kingdom; nDepartment of Pediatrics, Division of Pediatric Cardiology, Mayo Clinic, Rochester, Minnesota; oDivision of Pediatric Cardiology, Cleveland Clinic Foundation, Cleveland, Ohio; pChildren’s Heart Centre, Charles University and Motol J A C C : C L I N I C A L E L E C T R O P H Y S I O L O G Y V O L . - , N O . - , 2 0 1 7 ª 2 0 1 7 B Y T H E A M E R I C A N C O L L E G E O F C A R D I O L O G Y F O U N D A T I O N P U B L I S H E D B Y E L S E V I E R I S S N 2 4 0 5 - 5 0 0 X / $ 3 6 . 0 0 h t t p s : / / d o i . o r g / 1 0 . 1 0 1 6 / j . j a c e p . 2 0 1 7 . 1 0 . 0 0 9 S udden death in Wolff-Parkinson- White (WPW) syndrome is a rare but potentially preventable problem affecting young, otherwise healthy people. Sudden death is usually a consequence of atrial fibrillation with rapid conduction over an accessory pathway resulting in ventricular fibrillation. Because WPW patients develop atrial fibrillation more frequently than the general population, an important question is whether there is a risk of ventricular fibrillation should atrial fibrillation occur. Assessing accessory pathway conduction properties by using electrophysiology study (EPS) is advocated as a preventive strategy against sudden death, as noninvasive risk stratification tools are imperfect (1–4). Inducible atrioventricular re-entrant tachycardia (AVRT) or EPS data suggesting a pathway capable of rapid anterograde conduction are identified as predictors of malignant arrhythmia (5–8). Because catheter ablation can cure WPW syndrome and eliminate risk (9), the small long-term risk of a lifethreatening event (LTE) must be balanced with the immediate albeit low risk of an ablation. The low event rate of WPW syndrome, reduced further by catheter ablation, makes risk assessment a challenge. Data investigating possible risk factors for LTE in children with WPW syndrome, however, remain critical. In this study, we compared children with WPW syndrome who had experienced an LTE with a control population (WPW syndrome without LTE) to identify characteristics associated with sudden death risk. METHODS This multicenter, international, retrospective casecontrol study involved 22 centers from 6 countries (United States, Canada, New Zealand, Cuba, Czech Republic, and Wales [United Kingdom]) solicited through the Pediatric and Congenital Electrophysiology Society (PACES). Data collected encompassed the era of catheter ablation in children, from January 1990 through June 2016. All centers obtained local investigational review board approval, and institutional databases were searched to identify children with WPW syndrome. De-identified data were managed using Research Electronic Data Capture (REDCap), hosted at the University of Utah. REDCap is a secure, Web-based application designed to support data capture for research (10). All data were reviewed by the data coordinating center and statistician for appropriateness for inclusion. CASE SUBJECTS. Case subjects were children with WPW syndrome who had experienced an LTE at #21 years of age. An LTE was defined as sudden death, aborted sudden death, or a clinical episode of preexcited atrial fibrillation with the shortest preexcited RR interval (SPERRI) in atrial fibrillation of #250 ms, regardless of symptoms or documented pre-excited atrial fibrillation associated with hemodynamic compromise, syncope, or seizure, regardless of the SPERRI. Subjects who experienced pre-excited atrial fibrillation without associated hemodynamic compromise, syncope, or seizure and a SPERRI >250 ms were excluded. Cases of sudden death were included if a pre-mortem electrocardiogram (ECG) and/or EPS proving WPW syndrome was available. CONTROL SUBJECTS. Control subjects were #21 years of age with WPW syndrome who had not experienced an LTE or clinical pre-excited atrial fibrillation and had undergone an EPS. For each case subject, 4 age-matched subjects (24 months of age at EPS or LTE if no EPS was performed) and 4 non–age-matched subjects were selected by each center. Two sets of subjects were selected to potentially mitigate and investigate influences of age and size on ablation outcomes and risk. Matched subjects were selected from the same institution when possible or from other participating centers. Except for analyses involving age, subjects were evaluated as a single control group. Congenital heart disease (CHD) was noted, but cases and subjects were not matched for this variable. A B B R E V I A T I O N S A N D A C R O N Y M S APERP = accessory pathway effective refractory period ART = antidromic reciprocating tachycardia AVRT = atrioventricular reciprocating tachycardia CHD = congenital heart disease EPS = electrophysiology study LTE = life-threatening event ORT = orthodromic reciprocating tachycardia SPERRI = shortest pre-excited RR interval in atrial fibrillation SPPCL = shortest pre-excited paced cycle length with atrial pacing SVT = supraventricular tachycardia WPW = Wolff-Parkinson-White syndrome University Hospital, Prague, Czech Republic; qDepartment of Pediatrics, Benioff Children’s Hospital, University of California San Francisco, San Francisco, California; rDivision of Pediatric Cardiology, Texas Children’s Hospital, Baylor College of Medicine, Houston Texas; sNationwide Children’s Hospital, Columbus, Ohio; tDivision of Pediatric Cardiology in the Department of Pediatrics, Children’s Hospital and Medical Center, Omaha, Nebraska; uDepartment of Pediatrics, Division of Pediatric Cardiology, UCLA Medical Center, University of California Los Angeles, Los Angeles, California; vPhoenix Children’s Hospital, University of Arizona College of Medicine, Phoenix, Arizona; and the wDivision of Cardiology, Department of Pediatrics, British Columbia Children’s Hospital, Vancouver, British Columbia, Canada. Dr. Kubus is supported by the Ministry of Health, Czech Republic (MHCZ-DRO), University Hospital Motol, Prague, Czech Republic 00064203. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received August 16, 2017; revised manuscript received October 3, 2017, accepted October 12, 2017. Etheridge et al. J A C C : C L I N I C A L E L E C T R O P H Y S I O L O G Y V O L . - , N O . - , 2 0 1 7 Life-Threatening Event Risk in Children With WPW Syndrome - 2 0 1 7 : - – - 2 CLINICAL DATA Demographic data included age at presentation, EPS information, and last follow-up examination. Symptoms, documented supraventricular tachycardia (SVT), and hemodynamically significant CHD were noted. Hemodynamically insignificant ventricular and atrial septal defects, ductus arteriosus, mitral valve prolapse, isolated left superior vena cava, and bicuspid aortic valve without stenosis or insufficiency were not considered significant CHD. Details of the LTE were collected, including activity at the time (rest, active but noncompetitive, competitive activity, as determined by the contributing center), type of event (pre-excited atrial fibrillation, aborted sudden death or ventricular fibrillation, or sudden death), and outcome (death, full or near full recovery, or recovery with a neurological deficit). All cases were reviewed by the coordinating center. ELECTROPHYSIOLOGY STUDIES. By design, an EPS was performed in all subjects. If case subjects had >1 EPS performed, the earliest study with risk stratification data was included for analysis. EPS data collected included determination of conduction properties, location of pathway(s), and induction of tachycardia including orthodromic reciprocating tachycardia (ORT), antidromic reciprocating tachycardia (ART), atrioventricular node reentrant tachycardia, atrial flutter, or atrial fibrillation. We considered risk stratification as performing at least one of the following studies: accessory pathway effective refractory period (APERP), shortest paced cycle length with preexcitation during atrial pacing (SPPCL) or SPERRI. If the atrial effective refractory period (AERP) was reached before APERP, the AERP was used in place of APERP. An APERP, SPPCL, or SPERRI value of #250 ms was considered high-risk. The use of anesthesia was noted. Data for isoproterenol were reported when available. Ablation success and complications were reported. STATISTICAL ANALYSIS. Frequency tables were generated for all categorical variables (SPSS version 20.0, IBM Corp., Armonk, New York), with chi-square or Fisher exact analyses used to detect differences between case and control subjects. Mean and SD were reported for continuous variables. Univariate analysis of variance (ANOVA) was used to compare means for continuous variables between cases and subjects. Binomial logistic regression analyses were used to predict risk of LTE (i.e., cases vs. subjects) based on sex and at least one of following variables: APERP, SPERRI, or SPPCL #250 ms; presence of Ebstein malformation; inducible atrial fibrillation at EPS; or the presence of >1 accessory pathway. The EPSderived data were combined for logistic regression analysis because too few subjects had all 3 measurements determined. EPS data for univariate and multivariate analyses were obtained in the baseline state. Receiver-operating characteristic (ROC) curves were constructed to determine the sensitivity and specificity of different cutoff values of APERP, SPERRI, and SPPCL. For some analyses of tachycardia induction, ORT and ART were combined and designated AVRT. Significance was set at a p value of #0.05. RESULTS DEMOGRAPHIC DATA, ENTIRE COHORT. A total of 108 cases and 864 subjects were initially entered into the database, but 12 cases were excluded for not meeting LTE criteria. Thus, a total of 912 subjects (96 cases and 816 subjects) were analyzed (the 48 subjects age-matched to excluded subjects were omitted, but the non–age-matched subjects were TABLE 1 Characteristics of the Study Cohort Case Subjects (n ¼ 96) Control Subjects (n ¼ 816) p Value Values are mean SD, %, or n (%). *Non–age-matched subjects were used for analysis. CHD ¼ congenital heart disease; EPS ¼ electrophysiology study; LTE ¼ life-threatening event; NS ¼ not significant; SVT ¼ supraventricular tachycardia; WPW ¼ Wolff-Parkinson-White syndrome. Age at WPW presentation, yrs 11.5 6.1 9.7 5.3* 0.003 Males (%) 78 58 <0.0005 Race (%) Caucasian 67.7 73.2 NS African American 9.4 6.5 NS Native American, Alaskan Native, First Nations 1.0 0.4 NS Asian (%) 3.1 2.1 NS Hawaiian/Pacific Islander 1.0 1.7 NS >1 ethnic group 0 0.9 NS Symptoms before LTE/EPS (%) 60.0 83.9 <0.0005 chest pain 3.2 6.5 NS Syncope 15.1 10.8 NS Pre-syncope 5.3 5.8 NS Palpitations 47.4 68.4 <0.0005 Documented SVT (%) 25.5 44.2 0.001 CHD (%) 7.3 3.2 0.042 Follow-up, yrs From diagnosis 5.0 6.1 4.2 4.5 NS From LTE/EPS 2.3 3.6 1.4 1.8 <0.0005 Number alive at last follow-up (%) 87 (90.6) 100 (100.0) <0.0005 Death 9 (9) 0 (0) J A C C : C L I N I C A L E L E C T R O P H Y S I O L O G Y V O L . - , N O . - , 2 0 1 7 Etheridge et al. - 2 0 1 7 : - – - Life-Threatening Event Risk in Children With WPW Syndrome 3 retained). The 2 control groups did not differ except in age and were combined into a single group for all analyses except for age. Demographic and clinical data are summarized in Table 1. Case subjects were more likely to be male and were older at presentation than non–age-matched subjects. Case subjects were less likely to have experienced symptoms before the LTE than subjects and were more likely to have CHD. The most common lesion was Ebstein malformation (n ¼ 15), more prevalent in case subjects (5.2% vs. 1.2%, respectively; p ¼ 0.004). At last follow-up examination, there were 9 deaths, all in case subjects. CLINICAL DATA, CASE SUBJECTS. Table 2 outlines the characteristics of case subjects and LTE details. Mean age at LTE was 14.1 3.9 years of age with 3 subjects <5 years of age (Table 3). The LTE occurred most often at rest or with noncompetitive activity and was equally likely to be rapidly conducted pre-excited atrial fibrillation and aborted sudden death. There were 6 subjects (6%) who presented with sudden death who had a pre-mortem ECG and/or EPS demonstrate WPW syndrome, and post-mortem evaluation did not reveal an identifiable alternative cause of death. Three case subjects experienced 2 LTEs, and 1 had stable pre-excited atrial fibrillation before experiencing an LTE. Among case subjects, age <12 years (n ¼ 16) was associated with aborted sudden death as the LTE (88% vs 36%, p <0.0005) and age $12 years (n ¼ 80) was associated with pre-excited atrial fibrillation as the LTE (56% vs 13%, p ¼ 0.002). Clinical SPERRI was reported in 46 cases with preexcited atrial fibrillation as their LTE (1 was classified as aborted sudden death due to degeneration to ventricular fibrillation). The mean SPERRI was 202 33 ms (range 150 to 320 ms). Two case subjects had pre-excited atrial fibrillation and an unknown SPERRI, 1 with recurrent seizures requiring intubation and a second subject with poor perfusion and hypotension. An additional case subject had syncope while running and a clinical SPERRI upon presentation of 320 ms. Sudden death or aborted sudden death was the presenting symptom in 31 case subjects, and preexcited atrial fibrillation was the presenting symptom in 31 subjects. There were 38 (40%) of case subjects who had not complained of previous symptoms before the LTE. There were 56 case subjects (58%) who were not known to have WPW syndrome before the LTE. Of these, 32 (33%) were symptom free. The remaining 24 reported prior symptoms including documented SVT (n ¼ 1), palpitations alone (n ¼ 11), palpitations and syncope (n ¼ 5), palpitations and near syncope (n ¼ 4), and syncope alone (n ¼ 3). Full or near full recovery was likely in case subjects after LTE. Five subjects recovered with a neurological deficit; of these, 1 subject had acute kidney failure, and 1 had right leg compartment syndrome after extracorporeal membrane oxygenation support. The LTE was sudden death in 6 cases. Three additional cases were removed from life support due to devastating neurological injury. One death occurred in a child who became a heart transplant donor, and WPW syndrome was diagnosed in the recipient subsequent to transplantation. ELECTROPHYSIOLOGY STUDY DATA, ENTIRE COHORT. Table 4 outlines EPS data and ablation outcomes. EPS data were available in all subjects and TABLE 2 Clinical Characteristics of Case Subjects (N ¼ 96) Values are mean SD or n (%). Abbreviations as in Table 1. Age at LTE (yrs) 14.1 3.9 (range 0.4 months-21 yrs) Known WPW 40 (42) LTE as presenting symptom 62 (65) LTE diagnosis Pre-excited atrial fibrillation 47 (49) Aborted sudden death 43 (45) Sudden death 6 (6) Activity at time of LTE Rest 37 (39) Active, noncompetitive 33 (34) Active, competitive 10 (10) Unknown 16 (17) Outcome of the LTE Full/near full recovery 82 (85) Recovery with neurological injury 5 (5) Death 9 (9) TABLE 3 LTE in Children <5 Years of Age Age Event Details Outcome 0.6 month Aborted sudden death Resuscitated cardiac arrest after weeks of poor feeding Seizures, small cerebral hemorrhage. Awaiting EPS on therapy. 0.1 month Aborted sudden death Resuscitated cardiac arrest as first symptom EPS at 4.3 yrs with inducible ORT and successful ablation of midseptal AP. 2.4 yrs Ventricular fibrillation Known WPW patient presented with ventricular fibrillation while noncompliant with amiodarone EPS at 5.7 yrs inducible ORT and successful ablation of left lateral AP. AP ¼ accessory pathway; ECG ¼ electrocardiogram; ORT ¼ orthodromic reciprocating tachycardia; other abbre viations as in Table 1. Etheridge et al. J A C C : C L I N I C A L E L E C T R O P H Y S I O L O G Y V O L . - , N O . - , 2 0 1 7 Life-Threatening Event Risk in Children With WPW Syndrome - 2 0 1 7 : - – - 4 91% of cases. EPS data were not available in 8 case subjects, 7 of whom died without a previous EPS, and an infant who had yet to undergo EPS (Table 3). In 4 case subjects, EPS data were from a procedure performed before LTE. One case subject had EPS performed at a nonparticipating institution, and data were not available. One case subject was lost to follow-up after an acutely successful ablation. He presented in ventricular fibrillation with unsuccessful resuscitation. He had mild Ebstein malformation with trivial tricuspid regurgitation; autopsy findings were otherwise unremarkable. In the remaining 83 case subjects, EPS data were from a procedure after the LTE, including EPS and ablation data from a procedure performed in a recipient of a heart transplanted from a donor with WPW syndrome. Tachycardia induction. Table 4 outlines tachycardias induced. Case subjects were less likely to have ORT but more likely to have ART, atrial flutter, and atrial fibrillation. A ccessory pathway anterograde functional properties. Risk stratification, defined as the determination of accessory pathway anterograde functional property (APERP, SPERRI, or SPPCL) during EPS, was undertaken in 89% of case and 94% of control subjects. There were 60 of 87 case subjects (69%) who underwent an EPS with $2 accessory pathway functional properties determined. Case subjects had significantly shorter APERP, SPERRI, and SPPCL values and were more likely to have multiple accessory pathways (Table 4, Figure 1). Case subjects were more likely to have at least 1 functional property considered high-risk. There were values for EPSderived SPERRI reported in 39 (45%) of case subjects (mean 247 61 ms). However, in 14 of 39 (36%), the SPERRI was >250 ms. In 13 of these subjects, the procedure was performed using general anesthesia; in 1 subject, conscious sedation was used. This is not different from the group where the SPERRI was #250 ms, 18 had general anesthesia and 7 had conscious sedation (p ¼ 0.20). Among 60 case subjects who had risk stratification that included $2 accessory pathway characteristics, 22 of 60 (37%) did not have concerning pathway characteristics, and 15 of 60 (25%) had neither concerning pathway characteristics nor inducible AVRT. Figure 1 shows the proportion with pathway functional characteristics considered high-risk (APERP, SPERRI, or SPPCL of #250 ms) and with multiple accessory pathways. Figure 2 shows the distribution of EPS data in cases and subjects, and although there is overlap between case and subjects, a low-risk cutoff can be noted. No case subject had a SPERRI >370 ms or an APERP >400 ms. One case subject had a SPPCL >440 ms. Figure 3 demonstrates ROC curves for the risk stratification maneuvers and demonstrates no significant differences between the areas under the curve for each risk stratification maneuver. TABLE 4 Baseline EPS Data and Ablation Outcomes Case Subjects (n ¼ 96) Control Subjects (n ¼ 816) p Value Values are mean SD, n (%), or %. *Non–age-matched controls were included for analysis. APERP ¼ accessory pathway effective refractory period; ART ¼ antidromic reciprocating tachycardia; AVNRT ¼ atrioventricular node reentry tachycardia; AVRT ¼ atrioventricular reciprocating tachycardia; SPERRI ¼ shortest pre-excited RR interval in atrial fibrillation; SPPCL ¼ shortest paced cycle length with pre-excitation during atrial pacing; other abbreviations as in Table 1. Age at EPS, yrs 14.3 3.6 13.4 3.9* 0.042 EPS performed 87 (91) 816 (100) NS General anesthesia used (%) 86 87 NS SVT induced (%) 82 74 NS AVRT 56 64 NS ORT 52 63 0.035 ART 6 1 0.001 Atrial fibrillation 52 27 <0.0005 Atrial flutter 5 1 0.038 AVNRT 2.3 0.7 NS Risk stratification undertaken 77 (89) 766 (94) 0.056 APERP, ms 271 50 309 55 <0.0005 SPERRI, ms 247 61 315 77 <0.0005 SPPCL, ms 279 89 315 74 0.001 APERP #250 ms (%) 41 12 <0.0005 SPERRI #250 ms (%) 64 18 <0.0005 SPPCL #250 ms (%) 46 21 <0.0005 $1 functional measurement #250 ms 48 (62) 186 (24.5) <0.0005 >1 accessory pathway (%) 18.4 5.2 <0.0005 Ablation performed 85 (98) 789 (97) NS Ablation successful 71 (82) 353 (93) 0.001 Procedure complications 8 (9) 23 (3) 0.002 FIGURE 1 EPS-Derived Accessory Pathway Characteristics Percentage of case and control subjects with pathway characteristics suggesting high-risk (value #250 ms) is shown. *p # 0.05. AP ¼ accessory pathway; ms ¼ milliseconds; APERP ¼ accessory pathway effective refractory period; EPS ¼ electrophysiology study; SPERRI ¼ shortest pre-excited RR interval in atrial fibrillation; SPPCL ¼ shortest paced cycle length with pre-excitation during atrial pacing. In this graph on the X axis it should be >1 AP-I will be attaching a new version of this graph with this correction. J A C C : C L I N I C A L E L E C T R O P H Y S I O L O G Y V O L . - , N O . - , 2 0 1 7 Etheridge et al. - 2 0 1 7 : - – - Life-Threatening Event Risk in Children With WPW Syndrome 5 When EPS data from case subjects with pre-excited atrial fibrillation were compared to those of subjects with aborted sudden death, there were no significant differences in mean APERP, SPERRI, or SPPCL values and no differences in the proportion with any of these values #250 ms or the presence of multiple accessory pathways. Isoproterenol. EPS data during isoproterenol infusion were not available for the entire cohort (Table 5). Isoproterenol therapy resulted in a shortening of pathway functional properties in both groups, although case subjects continued to have significantly shorter SPERRI and SPPCL. Only 3 case subjects had all 3 functional characteristic studies performed while they were receiving isoproterenol therapy, too few to make meaningful conclusions. PREDICTORS OF LIFE-THREATENING EVENTS. Factors associated with LTE were identified by univariate analysis (Table 6), including APERP, SPERRI, and SPPCL #250 ms; presence of Ebstein malformation; inducible atrial fibrillation at EPS; and presence of multiple pathways. Logistic regression was statistically significant (chi-square: 5 ¼ 82.94; df ¼ 5, p < 0.0005). Table 7 outlines the features that were independently associated with increased odds of having an LTE. Of those who underwent EPS, ablation was attempted in 98% of cases and 97% of subjects. Success was lower in case subjects (82% vs. 93%, respectively; p ¼ 0.001). Table 8 outlines the pathway locations. More complications were noted in case subjects (Table 4), including atrioventricular block FIGURE 2 Distribution of EPS-Derived Data Box-and-whisker plots of APERP, SPERRI, and SPPCL in case and control subjects. Shown are mean values (solid line), and the standard deviations (thicker solid lines), and all values for data obtained, case subjects (red), and subjects (blue). The dotted line marks 250 ms. There were 2 outliers in which SPERRI was >600 ms (2 subjects) and 4 outliers (1 case and 3 subjects) with SPPCL >600 ms, these are not represented in the graphs. Abbreviations as in Figure 1. Etheridge et al. J A C C : C L I N I C A L E L E C T R O P H Y S I O L O G Y V O L . - , N O . - , 2 0 1 7 Life-Threatening Event Risk in Children With WPW Syndrome - 2 0 1 7 : - – - 6 (2.3% vs. 0.2%, respectively; p ¼ 0.048). There were no deaths resulting from EPS or ablation. DISCUSSION This multicenter, international study is the largest to have addressed pediatric WPW syndrome and has increased our understanding of risk. Although the children were treated in the contemporary era of catheter ablation, sudden death still occurred. An LTE was the sentinel event in 65%, with sudden death or aborted sudden death sentinel in nearly 1 of 3 subjects. Importantly, case subjects were less likely than subjects to have experienced previous symptoms. In this study, we sought to better characterize LTEs in children. Events occurred most often in adolescent males who were not engaged in competition. Although competitive athletics are considered to increase risk (11–14), sports restriction would not have prevented LTEs in the 73% of our case subjects whose FIGURE 3 ROC Curves (A) APERP, AUC ¼ 0.702 (95% CI: 0.633 to 0.770; p < 0.0005), and #250 ms has a sensitivity of 41% and specificity of 88% in differentiating between cases and subjects. (B) SPERRI, AUC ¼ 0.768 (95% CI: 0.679 to 0.858; p < 0.0005), and #250 ms has a sensitivity of 64% and specificity of 82% in differentiating between cases and subjects. (C) SPPCL, AUC ¼ 0.703 (95% CI: 0.629 to 0.778; p<0.0005), and #250 ms has a sensitivity of 46% and specificity of 79% in differentiating between cases and subjects. There were no significant differences in AUC among APERP, SPERRI, and SPPCL. AUC ¼ area under the curve; ROC ¼ receiver operating characteristic; other abbreviations as in Figure 1. J A C C : C L I N I C A L E L E C T R O P H Y S I O L O G Y V O L . - , N O . - , 2 0 1 7 Etheridge et al. - 2 0 1 7 : - – - Life-Threatening Event Risk in Children With WPW Syndrome 7 events did not occur with competition. Our data are consistent with previous series exploring sudden death in the young, where most events occurred during rest or sleep (15–17). The 10% of events occurring with sports, however, remains disproportionately high when one considers the percentage of time engaged in sports compared with time spent at rest and in noncompetitive activities. Thus, our data do not support unrestricted sports participation in patients with WPW syndrome but demonstrate that sports restriction does not keep children safe. Many studies have assessed pacing maneuvers for risk stratification. A prospective study found shorter APERP and degeneration into atrial fibrillation after AVRT were associated with development of malignant arrhythmias (9). Other studies have proposed that SPERRI best predicts risk, as patients with ventricular fibrillation had a SPERRI #250 ms (7). Our data suggest that substantial risk is present even without evidence of rapid anterograde pathway conduction at EPS, as commonly defined. Instead, the cutoff value at EPS identified in this cohort was higher: no case subject had an APERP >400 ms or a SPERRI >370 ms. KEY WORDS pediatrics, sudden death, Wolff-Parkinson-White syndrome J A C C : C L I N I C A L E L E C T R O P H Y S I O L O G Y V O L . - , N O . - , 2 0 1 7 Etheridge et al. - 2 0 1 7 : - – - Life-Threatening Event Risk in Children With WPW Syndrome 11