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Missing diagnosis of preexcitation syndrome on ECG
International Journal of Cardiology 163 (2013) 288–293
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International Journal of Cardiology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / i j c a r d
Missing diagnosis of preexcitation syndrome on ECG Clinical and electrophysiological significance Béatrice Brembilla-Perrot ⁎, Rouzbeh Valizadeh Moejezi, Pierre Yves Zinzius, Soumaya Jarmouni, Jérôme Schwartz, Daniel Beurrier, Jean Marc Sellal, Ibrahim Nossier, Lucian Muresan, Marius Andronache, Radou Moisei, Olivier Selton, Pierre Louis, Arnaud Terrier de la Chaise Department of cardiology, University Hospital of Brabois, Vandoeuvre, France
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Article history: Received 20 January 2011 Received in revised form 20 April 2011 Accepted 6 June 2011 Available online 24 June 2011 Keywords: Wolff–Parkinson–White syndrome ECG Electrophysiology Prognosis
a b s t r a c t Electrocardiographic criteria of preexcitation syndrome are sometimes not visible on ECG in sinus rhythm (SR). The purpose of the study was to evaluate the significance of unapparent preexcitation syndrome in SR, when overt conduction through accessory pathway (AP) was noted at atrial pacing. Methods: Anterograde conduction through atrioventricular AP was identified at electrophysiological study (EPS) in 712 patients, studied for tachycardia (n = 316), syncope (n = 89) or life-threatening arrhythmia (n = 55) or asymptomatic preexcitation syndrome (n = 252). ECG in SR at the time of EPS was analysed. Results: 78 patients (11%) (group I) had a normal ECG in SR and anterograde conduction over AP at atrial pacing; 634 (group II) had overt preexcitation in SR. Group I was as frequently asymptomatic (35%) as group II (35%), had as frequently tachycardias, syncope or life-threatening arrhythmia as group II (43, 5, 2% vs 43, 13, 8%). AP was more frequently left lateral in group I (57%) than in group II (36%)(p b 0.001). AV re-entrant tachycardia, atrial fibrillation (AF), antidromic tachycardia were induced as frequently in group I (54, 18, 10%) as in group II (54, 27, 7%). Malignant forms (induced AF with RR intervals between preexcited beats b250 ms in control state or b 200 ms after isoproterenol) were as frequent in group I (11.5%) as II (14%). Conclusions: The frequency of unapparent preexcitation syndrome represents 11% of our population with anterograde conduction through an AP and could be underestimated. The risk to have a malignant form is as high as in patients with overt preexcitation syndrome in SR. © 2011 Elsevier Ireland Ltd. All rights reserved.
Ventricular preexcitation syndrome is defined by the premature activation of all or part of the ventricles by atrial activity and is related to the presence of an atrioventricular (AV) accessory pathway (AP) [1]. These subjects might be asymptomatic, while other subjects have supraventricular arrhythmias; some of them may have potentially lethal arrhythmias with a low risk of 0.02%/patient/year [2]. The preexcitation syndrome is diagnosed by the surface ECG in sinus rhythm with a typical pattern associating a short PR interval (b0.12 s in adults) and a widening of QRS complex with a delta wave. It is often associated with disorders of repolarization. A pattern of preexcitation syndrome is noted among 0.1 to 0.5% of the population [3]. The pattern is dependent on the location of AP but also of the properties of AV node and His Purkinje system and there is a wide spectrum of ECG types encountered. Spontaneous normalization of ECG with intermittent preexcitation is reported in 20 to 30% of Wolff– Parkinson–White syndrome (WPW) [4,5]; dynamic QRS variations in Wolff–Parkinson–White syndrome were noted several years ago [6]. ⁎ Corresponding author at: Cardiology, University Hospital of Brabois, 54500 Vandoeuvre Les Nancy, France. Tel.: + 33 3 83 15 32 56; fax: + 33 3 83 15 42 26. E-mail address: [email protected] (B. Brembilla-Perrot). 0167-5273/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2011.06.051
Therefore, classical electrocardiographic criteria of preexcitation syndrome are sometimes not visible on ECG recorded in sinus rhythm. This can be very serious in athletes or in those with job as aviators, soldiers, driver… The purpose of the study was to evaluate the frequency and the significance of unapparent preexcitation syndrome in sinus rhythm, when an overt conduction through an accessory pathway was noted at atrial pacing.
1. Population A preexcitation syndrome related to an atrio ventricular accessory pathway was identified at electrophysiological study (EPS) among 712 patients, 431 males and 281 females, aged from 5 to 85 years (mean 34.5 ± 17). The subjects were examined consecutively by the same medical doctor in our department between 1990 and December 2010. The initial clinical presentation was as follows: Two hundred ninety seven patients had a known history of paroxysmal reciprocal tachycardia.
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Two hundred fifty two patients were asymptomatic: ventricular preexcitation syndrome was discovered during a systematic assessment before anaesthesia, before sporting license, prior to employment in certain occupations at risk or on an ECG performed in the preventive medicine. Among these subjects, 5 had a normal ECG and a preexcitation syndrome was noted at exercise testing indicated for a sport in 2 patients or to detect a coronary heart disease in 3 patients. Eighty nine patients presented unexplained syncope without documentation of any arrhythmia, event that was generally the initial cause leading to discover the ventricular preexcitation syndrome or to indicate the electrophysiological study. Nineteen patients presented with a documented well-tolerated spontaneous AF. AF was conducted only through normal AV conduction system in 13 patients and through accessory pathway and normal AV conduction system in 16 patients. Fifty five patients have an adverse presentation defined as a documented life-threatening haemodynamically not tolerated arrhythmia, with collapse or syncope and requiring a treatment in emergency related to a ventricular fibrillation (n=4), a rapid spontaneous antidromic tachycardia (n=5) and a rapid AF conducted through the accessory pathway at frequency higher than 250 bpm either spontaneously (n=49) or after use of verapamil (n=3).
Conduction over the accessory atrioventricular connection was evaluated by the measurement of the shortest atrial cycle length at which there was 1 to 1 conduction over the accessory connection and the shortest atrial tachycardia cycle length at which there was 1 to 1 conduction over the accessory connection. Accessory pathway's effective refractory period was determined at a cycle length of 600 ms and 400 ms in control state and only 400 ms after isoproterenol. Wolff–Parkinson–White syndrome was considered as malignant at electrophysiology study and at risk of sudden death when the following association was observed: the maximal heart rate with a 1 to 1 conduction over the accessory pathway was more than 240 bpm in control state or more than 290 bpm after isoproterenol infusion [14] during induced sustained atrial fibrillation. Orthodromic tachycardia induction alone was not considered as a criterium for a high risk form of preexcitation syndrome. The preexcitation syndrome was considered as benign if no tachycardia was induced and a 1 to 1 conduction over accessory pathway (AP) was less than 250 bpm in control state and less than 300 bpm after isoproterenol was noted.
2. Methods
Data are expressed as means ± standard deviation (SD). For categorical variables the chi-squared test was performed. The independent-sample t test procedure was used for continuous variables. The stepwise logistic regression was used to analyse the relationships between presence or not of a preexcitation syndrome at ECG in sinus rhythm (absence/presence = 0/1) as dependent variable and possible predictors (age, gender, accessory pathway location, the shortest cycle conducted through the accessory pathway, and inducibility before and after isoproterenol) as independent variables. A p value b 0.05 was considered statistically significant. All statistical analyses were performed by using the SPSS package for Windows (version 17. 0.1, SPSS Inc, Chicago, Illinois).
The data of ECG at the time of EPS and the data of EPS were retrospectively collected and studied. 1— Clinical data were collected. 2— The electrophysiological study was performed either by intracardiac route in symptomatic patients or only by the transesophageal route (n = 273) in out-patient clinic when these patients were asymptomatic or had unexplained syncope. In these patients, there was no indication of ablation or the patients refused the procedure. The patients were not sedated. Informed consent was obtained from the patients and in the case of children, from children and their parents. Our protocol was previously reported [7,8]. Briefly, incremental atrial pacing was performed until the highest rate conducted 1/1 through the accessory pathway and/or the AV node. Programmed atrial stimulation at a basic cycle length of 600 and 400 ms with the introduction of one and two extrastimuli was performed. In the absence of induction of a tachycardia conducted through the accessory pathway at a rate higher than 250 bpm, isoproterenol (0.02 to 1 μg min−1) was then infused to increase the sinus rate to at least 130 bpm and the pacing protocol was repeated. Arterial blood pressure was continuously monitored during the study by an external sphygmomanometer (Baxter, Japan).
3. Definitions Unapparent preexcitation syndrome was defined as a normal ECG at the time at electrophysiology which can be related to a masked preexcitation or an intermittent preexcitation. Masked preexcitation was defined as overt anterograde conduction through the accessory pathway masked by the normal AV conduction. These patients have a minimal preexcitation on the ECG that becomes apparent after ablation. Intermittent preexcitation was defined as a normal ECG related to a normal AV conduction recorded among patients who presented overt preexcitation on another ECG. The accessory pathway's location was determined with the 12 lead ECG recorded in maximal preexcitation. The diagnosis of multiple accessory pathways was retained only if AP's had different locations as left lateral and septal or right lateral and septal or left lateral and right lateral: in the left free wall location, the ablation could require the application of radiofrequency energy apparently at two sites, but it could be the same large accessory pathway. In the posteroseptal location left and right septal applications can be required to suppress the preexcitation. Sustained atrial fibrillation or reciprocating tachycardia was defined as a tachycardia that lasted more than one minute.
4. Statistical analysis
5. Results 5.1. 1—Prevalence of unapparent WPW Seventy-eight patients (11%) (group I) had a normal ECG in sinus rhythm at the time of EPS, but an anterograde conduction over AP occurred at atrial stimulation in the control state or after isoproterenol (Fig. 1). Among these patients, 24 patients had an intermittent preexcitation and EPS was indicated in 21 asymptomatic patients for this reason. The preexcitation syndrome became evident in 3 patients with masked preexcitation and 4 with intermittent preexcitation in sinus rhythm after isoproterenol. Nine patients with normal ECG in sinus rhythm had a patent preexcitation syndrome that occurs at exercise. But in 25 other patients for whom we could find exercise testing, there were no evident signs of preexcitation syndrome during the test. The data of remaining 634 patients (group II) with overt preexcitation in sinus rhythm were compared with the group I data. 5.2. 2—Clinical data (Table 1) Age was similar in both groups. The gender was similar: male gender was noted as frequently in group I (60%) as in group II (60.5%). Clinical presentations were similar (Table 1): group I as frequently asymptomatic (35%) as group II (35%); asymptomatic patients were studied for intermittent preexcitation syndrome (n = 21) or occurrence of a preexcitation syndrome at exercise test (n = 5). Therefore patients with intermittent preexcitation are more frequently asymptomatic than
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Fig. 1. Patient with a normal ECG; conduction through a patent left lateral AP and induction of an antidromic reciprocating tachycardia.
patients with masked preexcitation syndrome or remaining patients (pb 0.0001). Spontaneous re-entrant tachycardias tended to be more frequent in group I than in group II but the differences were not significant (p b 0.054) They were significantly more frequent in patients with masked preexcitation than in group II (p b 0.0001) and in patients with intermittent preexcitation (p b 0.0001). The feeling of tachycardia was the reason of EPS indication and of the discovery of the preexcitation syndrome. Spontaneous atrial fibrillation, unexplained syncope and adverse presentation were as frequent in groups I and II. Among these patients, three with masked preexcitation syndrome had as first event an adverse presentation. One patient, 20 years old presented ventricular fibrillation as the first event. After resuscitation, the ECG remained normal during 3 days without drugs. Then inconspicuous signs of preexcitation were discussed. A malignant form of WPW syndrome was identified at electrophysiological study which was indicated to understand the mechanism of ventricular fibrillation. A 55 years old woman had a syncope related to a rapid AF. Another woman, 17 years old presented with a rapid and poorly-tolerated AF. After regularisation, the ECG was normal or near normal with a PR interval of more 120 ms and a normal QRS duration. This is only after AP ablation that it was possible to find
the signs of masked anterograde conduction through the AP with small changes of the QRS pattern (Fig. 2): generally a small q wave appears in leads II, III, aVF and the R wave in V1 decreases. Remaining patients with adverse presentation had signs of preexcitation syndrome in sinus rhythm. AP was more frequently left lateral sided in group I (57%) than in group II (36%) (p b 0.001). This location was more frequent in patients with masked preexcitation than in remaining patients. However 26 patients (33%) had a septal AP (Fig. 3) and the septal location only tended to be less frequent than in group II (p b 0.059). In group I, one patient with intermittent preexcitation had also AV nodal re-entrant tachycardia. In group II 3 patients had 2 accessory pathway's and 2 patients had also AV nodal re-entrant tachycardia. 5.3. 3—Electrophysiological data (Table 1): In group I studied by intracradiac study, 5 patients with intermittent preexcitation and 32 with masked preexcitation, His-activation was earlier than the first ventricular activation but we have noted a mild increase of HV interval after ablation. Atrioventricular re-entrant tachycardia (AVRT) was induced as frequently in group I (54%) as in group II (54%) (NS). The patients with
Table 1 Clinical and electrophysiological data of groups I and II. PS: preexcitation syndrome; AP: accessory pathway, AF: atrial fibrillation, AVRT: AV re-entrant tachycardia, ADT: antidromic tachycardia, ERP: effective refractory period measured at a cycle length of 400 ms, CS: control state, iso: isoproterenol) * p b 0.05; ** p b0.01, *** p b 0.001: the data of group I or patients with masked preexcitation or intermittent preexcitation are compared with the data of group II.
Number Age (years) Male gender Asymptomatic Spontaneous tachycardia Syncope Spontaneous AF Adverse presentation Left lateral AP Septal AP Other locations Induced AVRT Induced AF Induced ADT Higher rate in CS bpm Higher rate after iso Malignant WPW AP ERP CS ms APERP isoproterenol
Group I
Group II
Masked PS
Intermittent PS
78 36 ± 17 47 (60%) 27 (35%) 41 (52.5%) 5 (6%) 2 (2.5%) 3 (4%) 44 (57%)*** 26 (33%)* 8 (10%) 42 (54%) 14 (18%) 8 (10%) 146 ± 75*** 195 ± 84*** 9 (11.5%) 326.5 ± 98** 231 ± 41
634 34 ± 17 384 (60.5%) 225 (35%) 256 (40%) 84 (13%) 17 (3%) 52 (8%) 226 (35.6%) 295 (46.4%) 113 (18%) 344 (54%) 169 (27%) 47 (7%) 196 ± 60 242 ± 66 90 (14%) 280.5 ± 68 222 ± 43
54 36 ± 17 31 (58%) 6 (11%) 39 (72. %)*** 4 (7%) 2 (4%) 3 (6%) 33 (61%)*** 16 (30%)* 5 (9%) 37 (68.5%) 14 (26%) 7 (13%) 168 ± 75*** 212 ± 86** 9 (17%) 301.5 ± 84 211.5 ± 28
24 34 ± 16 16 (67%) 21 (91%)*** 2 (8%) 1 (4%) 0 0 11 (45.8%) 10 (41.7%) 3 (12.5%) 5 (21%)** 0 1 (4%) 97 ± 44** 161 ± 71* 0 374 ± 110 260 ± 40*
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E
Fig. 2. ECG before (on the left) and after AP ablation (on the right); the presence of anterograde conduction through an AP becomes evident after ablation. The arrows indicate in II the loss of delta wave and in V1, the loss of r wave.
masked preexcitation differed from patients with intermittent preexcitation by a significantly higher rate of AVRT's induction (68.5% vs 21%, p b 0.0002). Among patients with intermittent preexcitation, AVRT was induced in control state in 4 patients complaining of tachycardia, after isoproterenol in one asymptomatic patient. Among patients with
masked preexcitation, AVRT was induced in control state in 27 patients, 3 with syncope, 22 with spontaneous tachycardias, one with AF, one with adverse event. AVRT was induced after isoproterenol in 10 patients with spontaneous tachycardias, 2 asymptomatic patients, one with spontaneous AF. Among group II patients, AVRT was induced in control
Fig. 3. Masked preexcitation in a patient with right posteroseptal AP; major preexcitation appeared at atrial pacing. The arrow pointed the AP refractory period; axis modification can be noted.
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state in 246 patients, 27 with syncope, 175 with spontaneous tachycardias, 12 asymptomatic patients, six with AF and 26 with adverse event. AVRT was induced after isoproterenol in 98 patients, 15 with syncope, 56 with spontaneous tachycardias, 19 asymptomatic patients, 4 with spontaneous AF and 4 with adverse event. Atrial fibrillation (AF) was induced as frequently in group I (18%) as in group II (27%) (0.06, NS). AF induction was noted only in patients with masked preexcitation (26%) and never in patients with intermittent preexcitation; AF was induced in control state in 11 patients, 8 with spontaneous re-entrant tachycardia, 3 with adverse event and in 3 patients complaining of re-entrant tachycardia after isoproterenol. Among group II patients, AF was induced in control state in 127 patients, 13 with syncope, 41 with spontaneous tachycardias, 31 asymptomatic patients, 10 with AF and 32 with adverse event. AF was induced after isoproterenol in 42 patients, 4 with syncope, 1 with spontaneous tachycardias, one asymptomatic patient, one with spontaneous AF and 6 with adverse event. Antidromic reciprocating tachycardia (ADT) was induced as frequently in groups I and II. A woman, 39 years old, with intermittent preexcitation had inducible antidromic tachycardia after isoproterenol at a rate of 260 bpm. The woman had no signs of preexcitation syndrome at exercise testing which was performed just after the EPS. Among patients with masked preexcitation, ADT was induced in 2 patients in control state and 5 after isoproterenol. All patients complained of re-entrant tachycardia. Among group II patients, ADT was induced in control state in 23 patients, 3 with syncope, 11 with spontaneous tachycardias, 4 asymptomatic patients, one with AF and 4 with adverse event. AF was induced after isoproterenol in 24 patients, 4 with syncope, 6 with spontaneous tachycardias, 9 asymptomatic patient and 5 with adverse event. The higher rate conducted through the AP in control state and after isoproterenol was lower in group I than in group II. However, the number of malignant forms was similar in group I (11.5%) and in group II (14%) (NS). Malignant form was identified in control state in 6 of 9 in group I and 56 of 89 in group II and only after isoproterenol in remaining patients.
6. Discussion The frequency of unapparent preexcitation syndrome represents 11% of our population with anterograde conduction through an AP and could be underestimated. The risk to have an electrophysiological malignant form was as high as in patients with overt preexcitation syndrome in sinus rhythm. Among these patients who had several ECG's, some have intermittent preexcitation and we confirm that asymptomatic patients with intermittent prexcitation have generally a good prognosis, as previously reported [4]. However, intermittent preexcitation does not exclude the induction of a re-entrant tachycardia, which is a factor of risk of arrhythmias for Pappone and al [9]. Remaining patients had a masked preexcitation. To miss a preexcitation syndrome on the surface ECG appears possible. At least 52 patients did not have the criteria of a preexcitation syndrome and this is only after ablation, that it was possible to retropectively identify minor signs of preexcitation on ECG in sinus rhythm. These patients had the same risk as the patients with an overt prexcitation syndrome. Several probable mechanisms explain the dynamic variability of the QRS complex observed in the WPW syndrome [10]. The importance of ventricular preexcitation on ECG in sinus rhythm depends on the quality of the nodohisian conduction and the distance between the accessory pathway and the normal conduction system [5]. More AP is located away from the sinus node and the normal atrioventricular system, less ventricular preexcitation is visible. Most of our patients had a left lateral AP, but some of them had septal AP's and we have no explanation for the absence of clear sign of preexcitation in sinus rhythm.
Another explanation for the intermittent loss of the delta wave in the Wolff–Parkinson–White (WPW) syndrome may result from precarious conduction over the AP and, as such, would predict a benign prognosis in the event of the occurrence of atrial fibrillation (AF). These patients have longer effective refractory periods of the AP and longer shortest cycle lengths maintaining 1:1 anterograde conduction than their counterparts with constant preexcitation. Therefore, intermittent preexcitation suggests a benign prognosis in the event of AF [4]. Concealed conduction in anomalous AV bypass tracts can be demonstrated in both anterograde and retrograde directions in most patients with WPW syndrome and is an important factor in the clinical expression of their arrhythmias [11,12]. Fig. 4 illustrates a case of intermittent preexcitation induced by a ventricular premature beat and related to the possible occurrence of a retrograde conduction through the normal conduction system inhibiting the next anterograde conduction through the His Purkinje system. Changes in atrioventricular conduction may account for the variability of the QRS pattern in patients with the WPW syndrome [13]. Spontaneous impairment of accessory pathway conduction due to phase 3 and phase 4 block was suspected [14,15]. Several pharmacological tests were proposed to enhance the pattern of preexcitation syndrome. Under the influence of exercise or emotion, patients with intermittent preexcitation may be at risk for serious arrhythmias [16]. The preexcitation syndrome appears in 9 of our patients under exercise. Therefore several authors recommend the use of isoproterenol; isoproterenol facilitates anterograde and retrograde accessory pathway conduction, but the facilitation of anterograde conduction occurs only in those capable of spontaneous conduction [17,18]. The method was used to differentiate the concealed accessory pathway which has lost its anterograde conduction from the masked or intermittent WPW syndrome. In the present study, the preexcitation syndrome became evident in only 3 patients with masked preexcitation and 4 with intermittent preexcitation in sinus rhythm after isoproterenol but was present at atrial pacing in all patients. The need for isoproterenol could have been higher in patients studied by intracardiac route. In our experience patients are generally stressed at the beginning of transesophageal study, so they have more vagotonic reactions during intracardiac study. Adenosine by blocking the conduction in the AV node was used to unmask a preexcitation syndrome [19,20], but was not used in the present study. Electrophysiological study and atrial pacing remain the most reliable technique to identify anterograde conduction through an accessory pathway [21]. The clinical interest of unmasking an accessory pathway is evident. In some patients anterograde conduction across a previously undocumented AP can be exposed by the development of atrial fibrillation, illustrating the possible unmasking of the WPW syndrome by other factors in patients who have not previously demonstrated the potential for anterograde AP conduction [22]. Sudden death may be caused by unusually atrial fibrillation conducted very fast by an AP with degeneration into ventricular fibrillation [23–25]; sudden death could be the first event in the evolution of this syndrome. This study reflects the difficulty of the interpretation of the surface ECG and the risk to miss a masked preexcitation syndrome at risk of adverse events, mainly among subjects who hide their symptoms. Limitations of the study: Some data are retrospective and then are limited bias of selection. A prospective study design could help to define the exact frequency of unapparent preexcitation syndrome. The separation of masked and intermittent preexcitation syndrome is debatable; it depends of the number of ECG recordings's; the pattern of preexcitation syndrome may vary from one ECG to another. Adenosine and carotid sinus massage were not used. In conclusion, the criteria for a prrexcitation syndrome pattern (PQ b 120 ms and a widening of the QRS complex with delta wave) are
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Fig. 4. Intermittent preexcitation syndrome. Anterograde conduction through the AP occurs after a ventricular premature beat; a possible explanation is the occurrence of a retrograde conduction through the normal conduction system inhibiting the next anterograde conduction through the His Purkinje system.
not sensitive enough to diagnose an accessory pathway particularly if it is left lateral sided. The frequency of unapparent preexcitation syndrome related to an AV AP represents 11% of our population with anterograde conduction through the AP, and could be underestimated. The risk to have a malignant form is as high as in patients with overt preexcitation syndrome in sinus rhythm. The ECG expression of preexcitation syndrome varies during the time for several reasons and can be misdiagnosed, when malignant form is possible. It is recommended repeating the ECG recordings in subjects who practice sports or have a profession with a high level of sportive activity to avoid missing a preexcitation syndrome. Moreover, do not hesitate to indicate an electrophysiological study in a patient who complains of tachycardia. Acknowledgement The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology. References [1] Anderson RH, Becker AE, Brechenmacher C, Davies MJ, Rossi L. Ventricular preexcitation. A proposed nomenclature for its substrates. Eur J Cardiol 1975;3:27–36. [2] Fitzsimmons PJ, Mc Whirter PD, Peterson DW, Kruyer WB. The natural history of Wolff–Parkinson–White syndrome in 228 military aviators: a long-term follow-up of 22 years. Am Heart J 2001;142:530–6. [3] Pelliccia A, Culasso F, Di Paolo FM, et al. Prevalence of abnormal electrocardiograms in a large, unselected population undergoing pre-participation cardiovascular screening. Eur Heart J 2007;28:2006–10. [4] Klein GJ, Gulamhusein SS. Intermittent preexcitation in the Wolff–Parkinson– White syndrome. Am J Cardiol 1983;52:292–6. [5] Garcia OL, Castellanos A, Vagueiro MC, Myerburg RJ, Gelband H. Arrival of excitation at the left ventricular apical endocardium in W.P.W syndrome type B. J Electrocardiol 1982;15:165–72. [6] Hindman MC, Last JH, Rosen KM. W.P.W. syndrome observed by portable monitoring. Ann Int Med 1973;79:654–63. [7] Brembilla-Perrot B, Chometon F, Groben L, et al. Interest of non-invasive and semi-invasive testings in asymptomatic children with pre-excitation syndrome. Europace 2007;9:837–43. [8] Brembilla-Perrot B, Tatar C, Suty-Selton C. Risk factors of adverse presentation as the first arrhythmia in Wolff–Parkinson–White syndrome. PACE; 2010. may 11.
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International Journal of Cardiology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / i j c a r d
Missing diagnosis of preexcitation syndrome on ECG Clinical and electrophysiological significance Béatrice Brembilla-Perrot ⁎, Rouzbeh Valizadeh Moejezi, Pierre Yves Zinzius, Soumaya Jarmouni, Jérôme Schwartz, Daniel Beurrier, Jean Marc Sellal, Ibrahim Nossier, Lucian Muresan, Marius Andronache, Radou Moisei, Olivier Selton, Pierre Louis, Arnaud Terrier de la Chaise Department of cardiology, University Hospital of Brabois, Vandoeuvre, France
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Article history: Received 20 January 2011 Received in revised form 20 April 2011 Accepted 6 June 2011 Available online 24 June 2011 Keywords: Wolff–Parkinson–White syndrome ECG Electrophysiology Prognosis
a b s t r a c t Electrocardiographic criteria of preexcitation syndrome are sometimes not visible on ECG in sinus rhythm (SR). The purpose of the study was to evaluate the significance of unapparent preexcitation syndrome in SR, when overt conduction through accessory pathway (AP) was noted at atrial pacing. Methods: Anterograde conduction through atrioventricular AP was identified at electrophysiological study (EPS) in 712 patients, studied for tachycardia (n = 316), syncope (n = 89) or life-threatening arrhythmia (n = 55) or asymptomatic preexcitation syndrome (n = 252). ECG in SR at the time of EPS was analysed. Results: 78 patients (11%) (group I) had a normal ECG in SR and anterograde conduction over AP at atrial pacing; 634 (group II) had overt preexcitation in SR. Group I was as frequently asymptomatic (35%) as group II (35%), had as frequently tachycardias, syncope or life-threatening arrhythmia as group II (43, 5, 2% vs 43, 13, 8%). AP was more frequently left lateral in group I (57%) than in group II (36%)(p b 0.001). AV re-entrant tachycardia, atrial fibrillation (AF), antidromic tachycardia were induced as frequently in group I (54, 18, 10%) as in group II (54, 27, 7%). Malignant forms (induced AF with RR intervals between preexcited beats b250 ms in control state or b 200 ms after isoproterenol) were as frequent in group I (11.5%) as II (14%). Conclusions: The frequency of unapparent preexcitation syndrome represents 11% of our population with anterograde conduction through an AP and could be underestimated. The risk to have a malignant form is as high as in patients with overt preexcitation syndrome in SR. © 2011 Elsevier Ireland Ltd. All rights reserved.
Ventricular preexcitation syndrome is defined by the premature activation of all or part of the ventricles by atrial activity and is related to the presence of an atrioventricular (AV) accessory pathway (AP) [1]. These subjects might be asymptomatic, while other subjects have supraventricular arrhythmias; some of them may have potentially lethal arrhythmias with a low risk of 0.02%/patient/year [2]. The preexcitation syndrome is diagnosed by the surface ECG in sinus rhythm with a typical pattern associating a short PR interval (b0.12 s in adults) and a widening of QRS complex with a delta wave. It is often associated with disorders of repolarization. A pattern of preexcitation syndrome is noted among 0.1 to 0.5% of the population [3]. The pattern is dependent on the location of AP but also of the properties of AV node and His Purkinje system and there is a wide spectrum of ECG types encountered. Spontaneous normalization of ECG with intermittent preexcitation is reported in 20 to 30% of Wolff– Parkinson–White syndrome (WPW) [4,5]; dynamic QRS variations in Wolff–Parkinson–White syndrome were noted several years ago [6]. ⁎ Corresponding author at: Cardiology, University Hospital of Brabois, 54500 Vandoeuvre Les Nancy, France. Tel.: + 33 3 83 15 32 56; fax: + 33 3 83 15 42 26. E-mail address: [email protected] (B. Brembilla-Perrot). 0167-5273/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2011.06.051
Therefore, classical electrocardiographic criteria of preexcitation syndrome are sometimes not visible on ECG recorded in sinus rhythm. This can be very serious in athletes or in those with job as aviators, soldiers, driver… The purpose of the study was to evaluate the frequency and the significance of unapparent preexcitation syndrome in sinus rhythm, when an overt conduction through an accessory pathway was noted at atrial pacing.
1. Population A preexcitation syndrome related to an atrio ventricular accessory pathway was identified at electrophysiological study (EPS) among 712 patients, 431 males and 281 females, aged from 5 to 85 years (mean 34.5 ± 17). The subjects were examined consecutively by the same medical doctor in our department between 1990 and December 2010. The initial clinical presentation was as follows: Two hundred ninety seven patients had a known history of paroxysmal reciprocal tachycardia.
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Two hundred fifty two patients were asymptomatic: ventricular preexcitation syndrome was discovered during a systematic assessment before anaesthesia, before sporting license, prior to employment in certain occupations at risk or on an ECG performed in the preventive medicine. Among these subjects, 5 had a normal ECG and a preexcitation syndrome was noted at exercise testing indicated for a sport in 2 patients or to detect a coronary heart disease in 3 patients. Eighty nine patients presented unexplained syncope without documentation of any arrhythmia, event that was generally the initial cause leading to discover the ventricular preexcitation syndrome or to indicate the electrophysiological study. Nineteen patients presented with a documented well-tolerated spontaneous AF. AF was conducted only through normal AV conduction system in 13 patients and through accessory pathway and normal AV conduction system in 16 patients. Fifty five patients have an adverse presentation defined as a documented life-threatening haemodynamically not tolerated arrhythmia, with collapse or syncope and requiring a treatment in emergency related to a ventricular fibrillation (n=4), a rapid spontaneous antidromic tachycardia (n=5) and a rapid AF conducted through the accessory pathway at frequency higher than 250 bpm either spontaneously (n=49) or after use of verapamil (n=3).
Conduction over the accessory atrioventricular connection was evaluated by the measurement of the shortest atrial cycle length at which there was 1 to 1 conduction over the accessory connection and the shortest atrial tachycardia cycle length at which there was 1 to 1 conduction over the accessory connection. Accessory pathway's effective refractory period was determined at a cycle length of 600 ms and 400 ms in control state and only 400 ms after isoproterenol. Wolff–Parkinson–White syndrome was considered as malignant at electrophysiology study and at risk of sudden death when the following association was observed: the maximal heart rate with a 1 to 1 conduction over the accessory pathway was more than 240 bpm in control state or more than 290 bpm after isoproterenol infusion [14] during induced sustained atrial fibrillation. Orthodromic tachycardia induction alone was not considered as a criterium for a high risk form of preexcitation syndrome. The preexcitation syndrome was considered as benign if no tachycardia was induced and a 1 to 1 conduction over accessory pathway (AP) was less than 250 bpm in control state and less than 300 bpm after isoproterenol was noted.
2. Methods
Data are expressed as means ± standard deviation (SD). For categorical variables the chi-squared test was performed. The independent-sample t test procedure was used for continuous variables. The stepwise logistic regression was used to analyse the relationships between presence or not of a preexcitation syndrome at ECG in sinus rhythm (absence/presence = 0/1) as dependent variable and possible predictors (age, gender, accessory pathway location, the shortest cycle conducted through the accessory pathway, and inducibility before and after isoproterenol) as independent variables. A p value b 0.05 was considered statistically significant. All statistical analyses were performed by using the SPSS package for Windows (version 17. 0.1, SPSS Inc, Chicago, Illinois).
The data of ECG at the time of EPS and the data of EPS were retrospectively collected and studied. 1— Clinical data were collected. 2— The electrophysiological study was performed either by intracardiac route in symptomatic patients or only by the transesophageal route (n = 273) in out-patient clinic when these patients were asymptomatic or had unexplained syncope. In these patients, there was no indication of ablation or the patients refused the procedure. The patients were not sedated. Informed consent was obtained from the patients and in the case of children, from children and their parents. Our protocol was previously reported [7,8]. Briefly, incremental atrial pacing was performed until the highest rate conducted 1/1 through the accessory pathway and/or the AV node. Programmed atrial stimulation at a basic cycle length of 600 and 400 ms with the introduction of one and two extrastimuli was performed. In the absence of induction of a tachycardia conducted through the accessory pathway at a rate higher than 250 bpm, isoproterenol (0.02 to 1 μg min−1) was then infused to increase the sinus rate to at least 130 bpm and the pacing protocol was repeated. Arterial blood pressure was continuously monitored during the study by an external sphygmomanometer (Baxter, Japan).
3. Definitions Unapparent preexcitation syndrome was defined as a normal ECG at the time at electrophysiology which can be related to a masked preexcitation or an intermittent preexcitation. Masked preexcitation was defined as overt anterograde conduction through the accessory pathway masked by the normal AV conduction. These patients have a minimal preexcitation on the ECG that becomes apparent after ablation. Intermittent preexcitation was defined as a normal ECG related to a normal AV conduction recorded among patients who presented overt preexcitation on another ECG. The accessory pathway's location was determined with the 12 lead ECG recorded in maximal preexcitation. The diagnosis of multiple accessory pathways was retained only if AP's had different locations as left lateral and septal or right lateral and septal or left lateral and right lateral: in the left free wall location, the ablation could require the application of radiofrequency energy apparently at two sites, but it could be the same large accessory pathway. In the posteroseptal location left and right septal applications can be required to suppress the preexcitation. Sustained atrial fibrillation or reciprocating tachycardia was defined as a tachycardia that lasted more than one minute.
4. Statistical analysis
5. Results 5.1. 1—Prevalence of unapparent WPW Seventy-eight patients (11%) (group I) had a normal ECG in sinus rhythm at the time of EPS, but an anterograde conduction over AP occurred at atrial stimulation in the control state or after isoproterenol (Fig. 1). Among these patients, 24 patients had an intermittent preexcitation and EPS was indicated in 21 asymptomatic patients for this reason. The preexcitation syndrome became evident in 3 patients with masked preexcitation and 4 with intermittent preexcitation in sinus rhythm after isoproterenol. Nine patients with normal ECG in sinus rhythm had a patent preexcitation syndrome that occurs at exercise. But in 25 other patients for whom we could find exercise testing, there were no evident signs of preexcitation syndrome during the test. The data of remaining 634 patients (group II) with overt preexcitation in sinus rhythm were compared with the group I data. 5.2. 2—Clinical data (Table 1) Age was similar in both groups. The gender was similar: male gender was noted as frequently in group I (60%) as in group II (60.5%). Clinical presentations were similar (Table 1): group I as frequently asymptomatic (35%) as group II (35%); asymptomatic patients were studied for intermittent preexcitation syndrome (n = 21) or occurrence of a preexcitation syndrome at exercise test (n = 5). Therefore patients with intermittent preexcitation are more frequently asymptomatic than
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Fig. 1. Patient with a normal ECG; conduction through a patent left lateral AP and induction of an antidromic reciprocating tachycardia.
patients with masked preexcitation syndrome or remaining patients (pb 0.0001). Spontaneous re-entrant tachycardias tended to be more frequent in group I than in group II but the differences were not significant (p b 0.054) They were significantly more frequent in patients with masked preexcitation than in group II (p b 0.0001) and in patients with intermittent preexcitation (p b 0.0001). The feeling of tachycardia was the reason of EPS indication and of the discovery of the preexcitation syndrome. Spontaneous atrial fibrillation, unexplained syncope and adverse presentation were as frequent in groups I and II. Among these patients, three with masked preexcitation syndrome had as first event an adverse presentation. One patient, 20 years old presented ventricular fibrillation as the first event. After resuscitation, the ECG remained normal during 3 days without drugs. Then inconspicuous signs of preexcitation were discussed. A malignant form of WPW syndrome was identified at electrophysiological study which was indicated to understand the mechanism of ventricular fibrillation. A 55 years old woman had a syncope related to a rapid AF. Another woman, 17 years old presented with a rapid and poorly-tolerated AF. After regularisation, the ECG was normal or near normal with a PR interval of more 120 ms and a normal QRS duration. This is only after AP ablation that it was possible to find
the signs of masked anterograde conduction through the AP with small changes of the QRS pattern (Fig. 2): generally a small q wave appears in leads II, III, aVF and the R wave in V1 decreases. Remaining patients with adverse presentation had signs of preexcitation syndrome in sinus rhythm. AP was more frequently left lateral sided in group I (57%) than in group II (36%) (p b 0.001). This location was more frequent in patients with masked preexcitation than in remaining patients. However 26 patients (33%) had a septal AP (Fig. 3) and the septal location only tended to be less frequent than in group II (p b 0.059). In group I, one patient with intermittent preexcitation had also AV nodal re-entrant tachycardia. In group II 3 patients had 2 accessory pathway's and 2 patients had also AV nodal re-entrant tachycardia. 5.3. 3—Electrophysiological data (Table 1): In group I studied by intracradiac study, 5 patients with intermittent preexcitation and 32 with masked preexcitation, His-activation was earlier than the first ventricular activation but we have noted a mild increase of HV interval after ablation. Atrioventricular re-entrant tachycardia (AVRT) was induced as frequently in group I (54%) as in group II (54%) (NS). The patients with
Table 1 Clinical and electrophysiological data of groups I and II. PS: preexcitation syndrome; AP: accessory pathway, AF: atrial fibrillation, AVRT: AV re-entrant tachycardia, ADT: antidromic tachycardia, ERP: effective refractory period measured at a cycle length of 400 ms, CS: control state, iso: isoproterenol) * p b 0.05; ** p b0.01, *** p b 0.001: the data of group I or patients with masked preexcitation or intermittent preexcitation are compared with the data of group II.
Number Age (years) Male gender Asymptomatic Spontaneous tachycardia Syncope Spontaneous AF Adverse presentation Left lateral AP Septal AP Other locations Induced AVRT Induced AF Induced ADT Higher rate in CS bpm Higher rate after iso Malignant WPW AP ERP CS ms APERP isoproterenol
Group I
Group II
Masked PS
Intermittent PS
78 36 ± 17 47 (60%) 27 (35%) 41 (52.5%) 5 (6%) 2 (2.5%) 3 (4%) 44 (57%)*** 26 (33%)* 8 (10%) 42 (54%) 14 (18%) 8 (10%) 146 ± 75*** 195 ± 84*** 9 (11.5%) 326.5 ± 98** 231 ± 41
634 34 ± 17 384 (60.5%) 225 (35%) 256 (40%) 84 (13%) 17 (3%) 52 (8%) 226 (35.6%) 295 (46.4%) 113 (18%) 344 (54%) 169 (27%) 47 (7%) 196 ± 60 242 ± 66 90 (14%) 280.5 ± 68 222 ± 43
54 36 ± 17 31 (58%) 6 (11%) 39 (72. %)*** 4 (7%) 2 (4%) 3 (6%) 33 (61%)*** 16 (30%)* 5 (9%) 37 (68.5%) 14 (26%) 7 (13%) 168 ± 75*** 212 ± 86** 9 (17%) 301.5 ± 84 211.5 ± 28
24 34 ± 16 16 (67%) 21 (91%)*** 2 (8%) 1 (4%) 0 0 11 (45.8%) 10 (41.7%) 3 (12.5%) 5 (21%)** 0 1 (4%) 97 ± 44** 161 ± 71* 0 374 ± 110 260 ± 40*
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Fig. 2. ECG before (on the left) and after AP ablation (on the right); the presence of anterograde conduction through an AP becomes evident after ablation. The arrows indicate in II the loss of delta wave and in V1, the loss of r wave.
masked preexcitation differed from patients with intermittent preexcitation by a significantly higher rate of AVRT's induction (68.5% vs 21%, p b 0.0002). Among patients with intermittent preexcitation, AVRT was induced in control state in 4 patients complaining of tachycardia, after isoproterenol in one asymptomatic patient. Among patients with
masked preexcitation, AVRT was induced in control state in 27 patients, 3 with syncope, 22 with spontaneous tachycardias, one with AF, one with adverse event. AVRT was induced after isoproterenol in 10 patients with spontaneous tachycardias, 2 asymptomatic patients, one with spontaneous AF. Among group II patients, AVRT was induced in control
Fig. 3. Masked preexcitation in a patient with right posteroseptal AP; major preexcitation appeared at atrial pacing. The arrow pointed the AP refractory period; axis modification can be noted.
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state in 246 patients, 27 with syncope, 175 with spontaneous tachycardias, 12 asymptomatic patients, six with AF and 26 with adverse event. AVRT was induced after isoproterenol in 98 patients, 15 with syncope, 56 with spontaneous tachycardias, 19 asymptomatic patients, 4 with spontaneous AF and 4 with adverse event. Atrial fibrillation (AF) was induced as frequently in group I (18%) as in group II (27%) (0.06, NS). AF induction was noted only in patients with masked preexcitation (26%) and never in patients with intermittent preexcitation; AF was induced in control state in 11 patients, 8 with spontaneous re-entrant tachycardia, 3 with adverse event and in 3 patients complaining of re-entrant tachycardia after isoproterenol. Among group II patients, AF was induced in control state in 127 patients, 13 with syncope, 41 with spontaneous tachycardias, 31 asymptomatic patients, 10 with AF and 32 with adverse event. AF was induced after isoproterenol in 42 patients, 4 with syncope, 1 with spontaneous tachycardias, one asymptomatic patient, one with spontaneous AF and 6 with adverse event. Antidromic reciprocating tachycardia (ADT) was induced as frequently in groups I and II. A woman, 39 years old, with intermittent preexcitation had inducible antidromic tachycardia after isoproterenol at a rate of 260 bpm. The woman had no signs of preexcitation syndrome at exercise testing which was performed just after the EPS. Among patients with masked preexcitation, ADT was induced in 2 patients in control state and 5 after isoproterenol. All patients complained of re-entrant tachycardia. Among group II patients, ADT was induced in control state in 23 patients, 3 with syncope, 11 with spontaneous tachycardias, 4 asymptomatic patients, one with AF and 4 with adverse event. AF was induced after isoproterenol in 24 patients, 4 with syncope, 6 with spontaneous tachycardias, 9 asymptomatic patient and 5 with adverse event. The higher rate conducted through the AP in control state and after isoproterenol was lower in group I than in group II. However, the number of malignant forms was similar in group I (11.5%) and in group II (14%) (NS). Malignant form was identified in control state in 6 of 9 in group I and 56 of 89 in group II and only after isoproterenol in remaining patients.
6. Discussion The frequency of unapparent preexcitation syndrome represents 11% of our population with anterograde conduction through an AP and could be underestimated. The risk to have an electrophysiological malignant form was as high as in patients with overt preexcitation syndrome in sinus rhythm. Among these patients who had several ECG's, some have intermittent preexcitation and we confirm that asymptomatic patients with intermittent prexcitation have generally a good prognosis, as previously reported [4]. However, intermittent preexcitation does not exclude the induction of a re-entrant tachycardia, which is a factor of risk of arrhythmias for Pappone and al [9]. Remaining patients had a masked preexcitation. To miss a preexcitation syndrome on the surface ECG appears possible. At least 52 patients did not have the criteria of a preexcitation syndrome and this is only after ablation, that it was possible to retropectively identify minor signs of preexcitation on ECG in sinus rhythm. These patients had the same risk as the patients with an overt prexcitation syndrome. Several probable mechanisms explain the dynamic variability of the QRS complex observed in the WPW syndrome [10]. The importance of ventricular preexcitation on ECG in sinus rhythm depends on the quality of the nodohisian conduction and the distance between the accessory pathway and the normal conduction system [5]. More AP is located away from the sinus node and the normal atrioventricular system, less ventricular preexcitation is visible. Most of our patients had a left lateral AP, but some of them had septal AP's and we have no explanation for the absence of clear sign of preexcitation in sinus rhythm.
Another explanation for the intermittent loss of the delta wave in the Wolff–Parkinson–White (WPW) syndrome may result from precarious conduction over the AP and, as such, would predict a benign prognosis in the event of the occurrence of atrial fibrillation (AF). These patients have longer effective refractory periods of the AP and longer shortest cycle lengths maintaining 1:1 anterograde conduction than their counterparts with constant preexcitation. Therefore, intermittent preexcitation suggests a benign prognosis in the event of AF [4]. Concealed conduction in anomalous AV bypass tracts can be demonstrated in both anterograde and retrograde directions in most patients with WPW syndrome and is an important factor in the clinical expression of their arrhythmias [11,12]. Fig. 4 illustrates a case of intermittent preexcitation induced by a ventricular premature beat and related to the possible occurrence of a retrograde conduction through the normal conduction system inhibiting the next anterograde conduction through the His Purkinje system. Changes in atrioventricular conduction may account for the variability of the QRS pattern in patients with the WPW syndrome [13]. Spontaneous impairment of accessory pathway conduction due to phase 3 and phase 4 block was suspected [14,15]. Several pharmacological tests were proposed to enhance the pattern of preexcitation syndrome. Under the influence of exercise or emotion, patients with intermittent preexcitation may be at risk for serious arrhythmias [16]. The preexcitation syndrome appears in 9 of our patients under exercise. Therefore several authors recommend the use of isoproterenol; isoproterenol facilitates anterograde and retrograde accessory pathway conduction, but the facilitation of anterograde conduction occurs only in those capable of spontaneous conduction [17,18]. The method was used to differentiate the concealed accessory pathway which has lost its anterograde conduction from the masked or intermittent WPW syndrome. In the present study, the preexcitation syndrome became evident in only 3 patients with masked preexcitation and 4 with intermittent preexcitation in sinus rhythm after isoproterenol but was present at atrial pacing in all patients. The need for isoproterenol could have been higher in patients studied by intracardiac route. In our experience patients are generally stressed at the beginning of transesophageal study, so they have more vagotonic reactions during intracardiac study. Adenosine by blocking the conduction in the AV node was used to unmask a preexcitation syndrome [19,20], but was not used in the present study. Electrophysiological study and atrial pacing remain the most reliable technique to identify anterograde conduction through an accessory pathway [21]. The clinical interest of unmasking an accessory pathway is evident. In some patients anterograde conduction across a previously undocumented AP can be exposed by the development of atrial fibrillation, illustrating the possible unmasking of the WPW syndrome by other factors in patients who have not previously demonstrated the potential for anterograde AP conduction [22]. Sudden death may be caused by unusually atrial fibrillation conducted very fast by an AP with degeneration into ventricular fibrillation [23–25]; sudden death could be the first event in the evolution of this syndrome. This study reflects the difficulty of the interpretation of the surface ECG and the risk to miss a masked preexcitation syndrome at risk of adverse events, mainly among subjects who hide their symptoms. Limitations of the study: Some data are retrospective and then are limited bias of selection. A prospective study design could help to define the exact frequency of unapparent preexcitation syndrome. The separation of masked and intermittent preexcitation syndrome is debatable; it depends of the number of ECG recordings's; the pattern of preexcitation syndrome may vary from one ECG to another. Adenosine and carotid sinus massage were not used. In conclusion, the criteria for a prrexcitation syndrome pattern (PQ b 120 ms and a widening of the QRS complex with delta wave) are
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Fig. 4. Intermittent preexcitation syndrome. Anterograde conduction through the AP occurs after a ventricular premature beat; a possible explanation is the occurrence of a retrograde conduction through the normal conduction system inhibiting the next anterograde conduction through the His Purkinje system.
not sensitive enough to diagnose an accessory pathway particularly if it is left lateral sided. The frequency of unapparent preexcitation syndrome related to an AV AP represents 11% of our population with anterograde conduction through the AP, and could be underestimated. The risk to have a malignant form is as high as in patients with overt preexcitation syndrome in sinus rhythm. The ECG expression of preexcitation syndrome varies during the time for several reasons and can be misdiagnosed, when malignant form is possible. It is recommended repeating the ECG recordings in subjects who practice sports or have a profession with a high level of sportive activity to avoid missing a preexcitation syndrome. Moreover, do not hesitate to indicate an electrophysiological study in a patient who complains of tachycardia. Acknowledgement The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology. References [1] Anderson RH, Becker AE, Brechenmacher C, Davies MJ, Rossi L. Ventricular preexcitation. A proposed nomenclature for its substrates. Eur J Cardiol 1975;3:27–36. [2] Fitzsimmons PJ, Mc Whirter PD, Peterson DW, Kruyer WB. The natural history of Wolff–Parkinson–White syndrome in 228 military aviators: a long-term follow-up of 22 years. Am Heart J 2001;142:530–6. [3] Pelliccia A, Culasso F, Di Paolo FM, et al. Prevalence of abnormal electrocardiograms in a large, unselected population undergoing pre-participation cardiovascular screening. Eur Heart J 2007;28:2006–10. [4] Klein GJ, Gulamhusein SS. Intermittent preexcitation in the Wolff–Parkinson– White syndrome. Am J Cardiol 1983;52:292–6. [5] Garcia OL, Castellanos A, Vagueiro MC, Myerburg RJ, Gelband H. Arrival of excitation at the left ventricular apical endocardium in W.P.W syndrome type B. J Electrocardiol 1982;15:165–72. [6] Hindman MC, Last JH, Rosen KM. W.P.W. syndrome observed by portable monitoring. Ann Int Med 1973;79:654–63. [7] Brembilla-Perrot B, Chometon F, Groben L, et al. Interest of non-invasive and semi-invasive testings in asymptomatic children with pre-excitation syndrome. Europace 2007;9:837–43. [8] Brembilla-Perrot B, Tatar C, Suty-Selton C. Risk factors of adverse presentation as the first arrhythmia in Wolff–Parkinson–White syndrome. PACE; 2010. may 11.
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