European Heart Journal Supplements (2015) 17 (Supplement A), A8–A11

The Heart of the Matter

doi:10.1093/eurheartj/suv004

The natural history of WPW syndrome

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Carlo Pappone*, Gabriele Vicedomini, Francesco Manguso, Mario Baldi,
Andrea Petretta, Luigi Giannelli, Massimo Saviano, Alessia Pappone,
Bogdan Ionescu, Cristiano Ciaccio, Raffaele Vitale, Amarild Cuko, Žarko Ćalović,
Angelica Fundaliotis, Mario Moscatiello, Concetto Catalano, and
Vincenzo Santinelli
Department of Arrhythmology, Department of Electrophysiology and Cardiac Pacing, Maria Cecilia Hospital,
GVM Care & Research, Via Corriera 1, Cotignola 20132, Italy

KEYWORDS The aim of this article is to understand the natural history of WPW syndrome to prevent
WPW syndrome; sudden death is important to clinicians in establishing accurate prognosis and appropri-
Sudden cardiac death; ate treatment. We report our experience on untreated WPW patients purely looking at
Ventricular fibrillation the natural history of the disease. In a 15-year period (1995–2010), among 11 237 WPW
patients referred to our Arrhythmology Department, a total of 1847 selected patients
(820 symptomatic) underwent electrophysiological testing without ablation and were
followed for a median (25th–75th) follow-up of 8 (5–8) years. During follow-up, malig-
nant arrhythmias (MA) occurred in 16 patients (0.9%) of whom 14 (1.4%) were initially
asymptomatic and two (0.2%) symptomatic (P ¼ 0.01). Potentially MA developed in
143 patients (7.7%) without difference between asymptomatic and symptomatic popula-
tion (P ¼ 0.663). Benign recurrences developed in 295 patients (16%) while ventricular
pre-excitation disappeared in 356 patients (19.3%) of whom 155 were initially asymptom-
atic. All patients were successfully ablated after arrhythmia occurrence. Patients
with MA had similar accessory pathways antegrade refractory periods (AP-AERP)
(P ¼ 0.064) and more frequently inducible atrioventricular reciprocating tachycardia
triggering atrial fibrillation (AVRT-AF) than those with potentially MA (P , 0.001). Symp-
toms did not predict MA, which were predicted by AP-AERP (HR 0.912, 95% CI
0.887–0.939, P , 0.001) and AVRT-AF (HR 8.306, 95% CI 2.269–30.405, P ¼ 0.001). The
natural history of WPW syndrome and the risk of sudden death essentially depend on
intrinsic electrophysiological accessory pathway properties rather than on symptoms
and electrophysiologic testing is the gold standard to identify patients at risk. The
Authors encourage more intensive screening programs to identify asymptomatic patients
at risk for prophylactic ablation.

Introduction patients has potentially malignant arrhythmias (MA) or

WPW patients have a low but lifetime risk of sudden death,
which can be eliminated by radiofrequency catheter abla-
tion of accessory pathways.1 Although critical risk factors
are well known, they are not specific since a minority of
* Corresponding author. Tel: +39 0545 217492, Fax: +39 0545 217108,
E-mail: cpappone@gvmnet.it
die limiting appropriate analysis of predictors.2,3 Defin-
ing ‘specific’ markers of the risk needs large prospective
studies of untreated WPW patients which in the era of cath-
eter ablation is difficult to collect representing a real chal-
lenge. The ACC/AHA/ESC guidelines recommend routine
electrophysiological testing (EPT) with a liberal indication
for catheter ablation only in the symptomatic WPW popula-
tion considering the presence of symptoms an important

Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2015.
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The natural history of WPW
prognostic risk factor.1 The initially asymptomatic WPW
population has been considered for many years to be at
minimal or no risk. As a result, prevention by intensive
screening programs to identify asymptomatic subjects at
potential risk has never been encouraged up to the last 10
years. More recent studies from our group in a large asymp-
tomatic patient population have reported that prognosis of
asymptomatic WPW subjects is not as benign as previously
supposed particularly in children,4–10 which suggested
performing more intensive screening and prevention pro-
grams.11,12 In the absence of an appropriate risk stratifica-
tion, the actual scenario is that many initially symptomatic
patients who are at low risk undergo unnecessary catheter
ablation while many others at potential risk may decline
or postpone ablation and then, untreated patients at risk
continue to experience devastating arrhythmias or die
suddenly. We report our long-term experience during the
last 15 years to better define the natural history of the
syndrome.
Methods
Between 1995 and 2010 all consecutive WPW patients who per-
formed at our Arrhythmology Department EPT without ablation
were collected purely looking at the natural history of WPW syn-
drome and predictors of outcome. As previously described,4–10
data collection includes prior clinical history, physical examin-
ation, 12-lead ECG, chest X-ray and echocardiography, an invasive
EPT and serial follow-up visits.
Electrophysiological study
Electrophysiological testing protocol has been previously des-
cribed in details.4–10 Atrial and ventricular extra-stimulation
with progressively shorter coupling intervals was performed
to induce atrioventricular re-entrant tachycardia (AVRT)
until the effective refractory periods of the atrium and ven-
tricle were achieved. Induction of atrial fibrillation was
attempted by ramp pacing starting at a cycle length of 300 up
to 200 ms. Inducible arrhythmias were defined as sustained if
they lasted more than 1 min. Tachyarrhythmia inducibility
was defined as reproducible induction of sustained AVRT and/
or atrial fibrillation (AF). There was a waiting period of 3 min
for AVRT to degenerate into AF. The anterograde effective
refractory period of the accessory pathway (AP-AERP) was
defined as the longest coupling interval at which anterograde
block in the bypass tract was observed. Multiple pathways
were diagnosed by accurate endocardial mapping during elec-
trophysiological study.
Definitions
A malignant arrhythmia was defined as ventricular fibrillation
or any tachyarrhythmia resulting in cardiac arrest. A potential-
ly malignant arrhythmia was defined as an episode of documen-
ted sustained (.1 min) AF with shortest pre-excited RR
interval (SPRRI) of ≤250 ms not resulting in cardiac arrest.
Cardiac arrest was considered as a condition requiring cardio-
pulmonary resuscitation and/or electrical defibrillation, not
associated with acute myocardial infarction or other transient
factors.
A9
Follow-up
Patients were followed without medical therapy or with medical or
ablation therapy at the discretion of the referring physicians once
arrhythmias occurred or recurred during follow-up. At each visit,
physical examination, 12-lead ECG, 24h Holter monitoring or
whenever clinical circumstances required unscheduled visits or
whenever they experienced symptoms suggestive of arrhythmias.
Clinical and follow-up data were collected before and after EPT,
with subsequent follow-up visits scheduled at 6, 12 months after
EPT, and yearly thereafter.
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Statistical analysis
We compared categorical outcomes by x 2 test. Continuous data
were expressed as mean + SD or median and 25th–75th percentile
according to the Gaussian distribution, and compared by using
the Unpaired t test or Mann–Whitney U test. Factors that predicted
MA after EPTwere identified by the Cox proportional hazards model
with backward-stepwise selection with the removal testing based
on the probability of the Wald statistic. Covariates included in the
model were sex (F/M ¼ 0/1), multiple pathways (no/yes ¼ 0/1),
inducibility of AVRT-AF (no/yes ¼ 0/1), AP-AERP, and symptoms
(no/yes ¼ 0/1). Statistical analysis was performed using IBM
SPSS Statistics version 22. Significance was accepted at P , 0.05.
All tests of significance were two sided.
Results
Among 11 237 consecutive WPW patients referred to our
Arrhythmology Department, 9390 patients (83.5%) under-
went RFA of accessory pathways. Of them, 8222 patients
performed only mapping and ablation of accessory path-
ways while the remaining 1168 patients underwent RFA
after a complete EPT. The remaining 1847 patients (820
symptomatic) underwent a complete electrophysiologic
testing without ablation according to the patient’ and
referring physician decision and were followed without
treatment constituting the study population. Before EPT
symptomatic patients had a first documented episode of
SVT, but malignant or potentially malignant arrhythmias
were never documented. Complete electrophysiologic
data were available for almost all patients (95%). Ortho-
dromic AVRT was reproducibly induced in all symptomatic
patients at baseline or after isoproterenol. Table 1 shows
the baseline clinical and electrophysiologic characteristics
of the study population. Overall, the mean age was 28.8 +
16.5 years with a male preponderance (1129 patients,
61.1%). Structural heart disease and multiple accessory
pathways were found in 6.7 and 5.8%, respectively. When
compared with the symptomatic subjects, the asymptom-
atic ones had a higher rate of inducibility of AVRT-AF
(14.3 vs. 2.9%, P , 0.001) and a preponderance of multiple
AP (8.4 vs. 2.6%; P , 0.001). The median follow-up was
8 (5–8) years.
Long-term outcome
During a median follow-up of 3 (2–3.75) years, malignant
arrhythmias occurred in 16 patients (0.9%) of whom 14
(1.4%) were initially asymptomatic and two (0.2%) symptom-
atic (P ¼ 0.01). During a median follow-up of 4 (3–5) years,
A10
Table 1 Characteristics and follow-up of 1847 untreated WPW patients
Total (n ¼ 1847)
Age (years) 25.8 + 15.0
Sex: Male (%) 1129 (61.1)
SHD, n (%) 124 (6.7)
Median APAERP, ms (25th–75th) 275 (260–300)
AVRT-AF, n (%) 171 (9.3)
Multiple AP, n (%) 107 (5.8)
Potentially MA, n (%) 143 (7.7)
MA, n (%) 16 (0.9)
Benign recurrences, n (%) 295 (16)
Age, age at enrolment; AP-AERP, accessory pathway antegrade effective refractory period at baseline; AVRT-AF, inducible atrioventricular re-entrant
tachycardia triggering atrial fibrillation at EPT; MA, malignant arrhythmias; Multiple AP, multiple accessory pathways; SHD, structural heart disease;
VF, ventricular fibrillation.
potentially malignant arrhythmias developed in 143 (7.7%)
additional patients without difference between the
asymptomatic and symptomatic population (P ¼ 0.663)
(Table 1). All of them were successfully ablated immedia-
tely after arrhythmia occurrence. Among patients who
had malignant arrhythmias, all but one had an AP-AERP
≤230 ms, as many as 75.4% had inducible AVRT triggering
AF and 27.5% showed multiple APs. Patients experienc-
ing malignant arrhythmias had shorter median AP-AERP
than those with potentially malignant arrhythmias [median
(25th–75th) 220 ms (210–230) vs. 240 ms (240–240);
P , 0.001] without difference in age, sex, and multiple
APs. Inducible AVRT triggering AF was more frequently
found in patients who had malignant arrhythmias (72.9
vs. 43.5%; P , 0.001). Malignant arrhythmias were pre-
ceded by warning symptoms including presyncope or dizzi-
ness. Potentially malignant arrhythmias were commonly
associated with palpitations, dizziness, light-headedness,
chest pain, or headache and were well tolerated in almost
all patients. During a median (25th–75th) follow-up of
8 (4–8) years, 295 patients (16%) with a median age of
17 years had benign recurrences including AVRT or AF and
all were successfully ablated after arrhythmia occurrence.
In addition, 356 patients (19.3%) with a median age of
39 years lost ventricular pre-excitation on the ECG remain-
ing asymptomatic. When compared with patients who did
not lose ventricular pre-excitation, they who did were
older with longer baseline AP-AERP (median, 300 vs. 270 ms,
P , 0.001).
Predictors of malignant arrhythmias
Predictors of malignant arrhythmias were short AP-AERP
(HR 0.912, 95% CI 0.887–0.939, P , 0.001) and AVRT-AF
(HR 8.306, 95% CI 2.269–30.405, P ¼ 0.001). The presence
of symptoms did not predict outcome.
Discussion
We report our experience on a unique large cohort of
untreated WPW patients undergoing electrophysiologic
testing without ablative procedure during a 15-year period
C. Pappone et al.
Asymptomatic (n ¼ 1027) Symptomatic (n ¼ 820) P-value
26.2 + 16.5 25.2 + 12.7 0.124
648 (63.1) 481 (58.7) 0.052
63 (6.1) 61 (7.4) 0.266
270 (250–300) 275 (260–290) 0.064
147 (14.3) 24 (2.9) ,0.001
86 (8.4) 21 (2.6) ,0.001
82 (8.0) 61 (7.4) 0.663
14 (1.4) 2 (0.2) 0.01
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132 (12.9) 163 (19.9) ,0.001
purely looking at the natural history of the disease. There
were 1027 asymptomatic patients and 820 initially symp-
tomatic untreated patients. Common predictors of both
malignant arrhythmias and potentially malignant arrhyth-
mias were inducibility of AVRT-AF and short AP-AERP but
not the presence of symptoms. These findings for the first
time indicate that intrinsic electrophysiologic properties
of accessory pathways and not symptoms constitute a ‘spe-
cific marker’ of the risk of sudden death in the whole WPW
population.
It is well known that WPW population has an excellent
outcome and that the risk of sudden death is very low,1
which suggests that risk stratification, particularly in the
asymptomatic population, is indeed important to decide
which patient should undergo prophylactic catheter abla-
tion contextually performed with EPT to eliminate
his/her lifetime risk.4–12 Once stratified, it is reasonable
that liberal indication to catheter ablation, as suggested
by current guidelines for all symptomatic patients, can be
reserved for patients at lower risk who represent the vast
majority of the WPW population.
Risk of sudden death in WPW syndrome
Although there are several published reports describing
devastatingly fatal arrhythmic events particularly in the
young population or asymptomatic children, the exact
risk of sudden death in patients with ventricular pre-
excitation is still unknown.1 Currently, in the era of wide-
spread use of catheter ablation it would be very challenging
or even impossible to conduct a long-term follow-up study
in untreated WPW population to shed light on incidence and
underlying mechanisms of potentially malignant arrhyth-
mias, which certainly represent the underlying cause of
sudden death leading to hemodynamic collapse and/or
cardiac arrest. Fortunately, not all WPW patients experien-
cing potentially malignant arrhythmias die depending on
circumstances (prompt resuscitation and/or cardiover-
sion, baseline low sympathetic tone, absence of structural
heart diseases, young age), which can underestimate the
potential risk of sudden death. A larger number of patients
and a more intensive monitoring are indeed crucial to
better define the real rate and risk of malignant arrhythmias,
The natural history of WPW
which in children can frequently occur with minimal atyp-
ical symptoms or no symptoms.6,8 In the last 10 years,
lacking ‘specific’ identifiable risk markers in the asymp-
tomatic children with WPW, most paediatric electrophy-
siologists have applied traditional general risk markers
to the asymptomatic paediatric population for prophylac-
tic ablation to prevent sudden death. According to our
experience, and regardless of symptoms we have identified
intrinsic electrophysiologic properties of accessory path-
ways as ‘specific’ markers of the risk, which are independ-
ent from the presence/absence of symptoms. Based on our
experience, a minority of initially asymptomatic WPW
patients with a characteristic electrophysiological profile
of accessory pathways is at risk of malignant arrhythmias
and this can explain why sudden death can be the first
clinical manifestation of the syndrome in the asymptomat-
ic population. These data strongly support and encourage
performing more intensive screening programs and risk
stratification to characterize and identify asymptomatic
WPW population, particularly children, as recently sug-
gested by two European surveys.11,12
Clinical implications
The results of this large study confirm that intrinsic electro-
physiologic properties of APs rather than the mere pres-
ence or absence of symptoms are the most important
parameter that should be considered in WPW patients. As
a result, EPT should be considered as the ‘gold standard’
to identify which patient is at higher risk, and accordingly
treated. Due to good prognosis of asymptomatic patients,
an electrophysiological study and contextually performed
RFA are suggested in case of arrhythmia or for professional
reasons (i.e. airplane pilot).
Conclusions
Our large experience over 15 years with nearly 2000
untreated WPW patients provides new insights on the
natural history of WPW syndrome in the era of catheter
ablation. Although the vast majority of the untreated
WPW subjects has a good outcome, a minority of them
can develop malignant or potentially malignant arrhyth-
mias. Intrinsic electrophysiologic properties of accessory
pathways, regardless of symptoms, identify subjects at
risk of sudden death. The authors encourage more inten-
sive screening programs for prophylactic catheter ablation
of potentially fatal accessory pathways, particularly in
the young asymptomatic population.
Conflict of interest: none declared.
A11
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