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Journal of the American College of Cardiology
2013 by the American College of Cardiology Foundation
Published by Elsevier Inc.
Vol. 62, No. 10, 2013
ISSN 0735-1097/$36.00
http://dx.doi.org/10.1016/j.jacc.2013.05.054
STATE-OF-THE-ART PAPER
What Do We Know About the
“Malignant Form” of Early Repolarization?
Arnon Adler, MD, Raphael Rosso, MD, Dana Viskin, Amir Halkin, MD, Sami Viskin, MD
Tel Aviv, Israel
There is an urgent need to identify electrocardiographic characteristics that differentiate the “benign early
repolarization pattern” from “malignant early repolarization.” In a previous paper, we considered the different
electrocardiographic elements of the early repolarization pattern and analyzed how they confer important prognostic
information. In the present article, we review more recent information regarding the importance of the contour of
the ST segment, with special emphasis on the currently termed malignant form and its value for risk stratification in
early repolarization. (J Am Coll Cardiol 2013;62:863–8) ª 2013 by the American College of Cardiology
Foundation
There is an urgent need to identify electrocardiogram
(ECG) characteristics that differentiate the “benign early
repolarization” (ER) pattern from “malignant early repolarization” (1,2). Whereas the former ECG pattern is frequently observed in healthy personsdparticularly young,
male (3–5), athletic (6,7), and of African-American origin
(4,8)dthe latter is clearly associated with idiopathic
ventricular fibrillation (VF) in case-control studies (9,10),
and with increased mortality (presumably from myocardial
ischemia-related arrhythmias) in population-based studies
(11–13).
In previous papers, we considered the ongoing debates
between basic scientists and clinical cardiologists regarding
the actual pathophysiology of early repolarization (14,15),
and we analyzed in detail the different ECG elements of
the ER pattern and discussed how they are likely to confer
prognostic information (2). In brief, ER consists of 2
components: prominent J waves and ST-segment elevation. Whereas a prominent J-wave is the noticeable finding
in idiopathic VF, often increasing in amplitude just before
arrhythmia onset (9,16,17), ST-segment elevation is the
feature emphasized in reports of benign ER (2). The
importance of the J wave notwithstanding, in the present
article we review more recent information regarding the
importance of the contour of the ST-segment, with
emphasis on the currently termed malignant form and its
value for risk stratification in ER.
From the Tel Aviv Medical Center and Sackler School of Medicine, Tel Aviv
University, Tel Aviv, Israel. The authors have reported they have no relationships
relevant to the contents of this paper to disclose.
Manuscript received April 26, 2013; accepted May 22, 2013.
Historical Aspects: Evolution of Concept of
Malignant (Horizontal) Versus Benign
(Rapidly Ascending) ST-Segment Morphology
Tikkanen et al. (6) were the first to focus on the contour of
the ST-segment in ER. To define a benign form, Tikkanen
et al. (6) initially studied 2 populations of healthy athletes,
knowing that ER is particularly frequent in this group who
generally enjoys an excellent prognosis. He found that the
vast majority of healthy athletes with ER (85% in 1 series
and 96% in the other) had a “rapidly ascending” ST-segment
blending with the T-wave (Fig. 1A). They naturally
assumed this rapidly ascending form to be benign. The
remaining minority of athletes with ER features an STsegment that remains flat, horizontal, or even descends
toward the T-wave (Fig. 1B). This “horizontal/descending”
pattern drew Tikkanen’s suspicion to a “potentially malignant” variant of ER. He tested that hypothesis by reanalyzing data from his landmark population study, which had
already demonstrated a highly significant association
between the presence of ER on the baseline electrocardiogram and arrhythmic mortality during long-term follow-up
(Fig. 2A) (11). Indeed, the association between ER and
increased arrhythmic death risk was found to be restricted to
persons with the horizontal pattern (Fig. 2B), whereas the
prognosis of persons with a rapidly ascending ST-segment
was similar to that of persons without ER (6) (see population studies section in following text).
Our interest in the horizontal versus rapidly ascending
classification by Tikkanen arose from a figure from a previously published article by Cappato et al. (18) (reproduced
here as Figs. 1C and 1D). The study by Cappato et al. (18)
was at odds with the accepted notion that ER in athletes is
invariably benign. In this case-control series, ER was more
prevalent among athletes with unexplained sudden death
864
Adler et al.
Malignant Form of Early Repolarization
than in a control group of healthy
athletes (18). The study has been
criticized because the incidence
ECG = electrocardiogram
of ER in the control group was
ER = early repolarization
lower than that observed in larger
MI = myocardial infarction
series of healthy athletes (1). The
VF = ventricular fibrillation
intriguing aspect of the article,
however, was that the original
figure showed 2 ECGs, 1 of a healthy athlete and 1 of an
athlete who eventually died suddenly. That figure (Figs. 1C
and 1D) shows that the healthy athlete with ER had a rapidly
ascending ST-segment, whereas the athlete with cardiac
arrest had the horizontal pattern. Obviously, no conclusions
can be drawn from the ECGs of 2 persons; nevertheless, it
was intriguing that this figure (Figs. 1C and 1D) was published before Tikkanen recognized the prognostic value of the
ST-segment morphology in adults with ER. With this in
mind, we reanalyzed our original case-control series of idiopathic VF (10) and found that the association between ER and
cardiac arrest was related to the fact that idiopathic VF patients
with J waves mostly had a horizontal ST-segment, whereas
healthy controls had primarily the rapidly ascending type
(Fig. 3) (19). Soon, additional studies on ER began reporting
the prognostic impact of the ST-segment morphology. Most
of these studies used the definition proposed by Tikkanen and
associates (6), allowing for legitimate comparisons across
studies. As often happens in medicine, the emerging picture is
less straightforward but very interesting. The evolving story is
presented herein, covering the various forms of ER, from the
most benign type, observed in healthy athletes, to the most
malignant pattern found in idiopathic VF (Fig. 4).
Early repolarization in athletes. Abundant data demonstrate that early repolarization is very common among young
athletes (1). Indeed, both the prevalence and magnitude of
ER in athletes increase as their training intensifies (7). Four
recent studies (6,7,10,18) provide data on ST-segment
morphology in 1,930 athletes. In these studies, the percentage of athletes with ER ranged from 23% to 44%. Yet,
in all but 1 study (18), the vast majority of unselected
athletes with ER had the rapidly ascending pattern and <5%
had ER with a horizontal ST-segment (Fig. 4).
Only 1 of the latter studies included athletes with malignant ventricular arrhythmias. This already alluded to study by
Cappato et al. (18) compared 21 athletes who sustained
a “cardiac arrest of unclear etiology despite extensive evaluation” to >300 healthy athletes. In this retrospective case
series, athletes with ER with no ST-segment elevation (which
is the equivalent of ER with horizontal ST-segment in the
Tikkanen classification [6]) were 11 times more likely to have
a cardiac arrest (18).
Population-based studies. Six studies (5,6,19–22) provide
data on the ST-segment morphology of 21,577 non-athlete
adults (Fig. 4). Here, the incidence of ER ranged from 5%
to 13%. Three of these studies were large population-based
studies involving thousands of adults (mean age z46 years)
(6,20,22). In these studies, the malignant form of ER was
JACC Vol. 62, No. 10, 2013
September 3, 2013:863–8
Abbreviations
and Acronyms
Figure 1
Electrocardiographic Examples of ER
(Top panel) Examples of early repolarization (ER) with (A) rapidly ascending and
(B) horizontal ST segment as presented in the landmark study by Tikkanen et al.
(6). Only the horizontal form (B) was associated with increased arrhythmic
mortality during long-term follow-up. (Middle panel) The 2 electrocardiograms
(ECGs) presented in the study by Cappato et al. (18) associating early repolarization with unexplained arrhythmic death in athletes: the ECG on the left (C) is
from a healthy athlete; the ECG on the right (D) is from an athlete who eventually
died suddenly. Note the J waves (arrows) and the ST-segment that is ascending in
the healthy athlete and horizontal in the athlete with cardiac arrest. (Lower panel)
The ECG (E) and activation-recovery sequence mapping performed with noninvasive computerized electrocardiographic imaging (F, G) in a 55-year-old man with
idiopathic ventricular fibrillation (VF) as published by Ghosh et al. (34). (E) Note the
J waves (arrows) and the horizontal ST-segment, best seen in aVF. The electrocardiographic imaging map was performed in sinus rhythm. (F) The sequence of
activation (depolarization) smoothly propagates from relatively early (green) to
relatively late (blue). (G) The sequence of repolarization (activation recovery
intervals) during sinus rhythm. Abnormal repolarization gradients are created
because zones of very early repolarization (red) are contiguous to area of later
repolarization (blue). LA ¼ left atrium; LAO ¼ left anterior oblique; LPO ¼ left
posterior oblique; RA = right atrium; RAO ¼ right anterior oblique.
actually the most prevalent: 4% to 9% of unselected adults
had ER with horizontal ST-segment whereas only 2% to 5%
had ER of the benign ascending type (Fig. 4) (6,20,22).
Furthermore, restricting this analysis only to adults with
ER shows that the majority of them (65% to 73%) had their
J waves followed by a horizontal ST-segment. At first
glance, the predominance of the horizontal ST-segment
among adults appears to contradict its malignant attribute.
JACC Vol. 62, No. 10, 2013
September 3, 2013:863–8
Figure 2
Adler et al.
Malignant Form of Early Repolarization
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Kaplan-Meier Survival Curves for Arrhythmic Death
(A) Kaplan-Meier survival curves for arrhythmic death among adults with early repolarization (ER) (red curve) and without ER (blue curve) in their baseline electrocardiogram
(ECG) as reported by Tikkanen et al. (11). (B) A subsequent analysis of the same data demonstrates that the association between ER at baseline with increased mortality during
long-term follow-up is due to a strong association between ER with horizontal ST segment (dotted line) and arrhythmic death (6). The arrhythmic mortality rate of persons with ER
of the ascending type (dashed line) is like that of persons without ER (solid line).
However, 2 of these studies (6,20) also correlated the pattern
of ER with long-term outcome, and in both, the presence of
malignant (horizontal) ST-segment was associated with
a worse prognosis. First, in the study by Tikkanen et al. (6),
subjects with ER had a higher risk for sudden death only
if their ST-segment was horizontal; for such patients the risk
of arrhythmic death was 1.42-fold higher (1.7-fold higher if
the horizontal ER was recorded in the inferior leads) (6). In
the more recent study by Rollin et al. (20) the presence of
ER in the inferior leads was associated with an almost
5-fold higher risk for cardiovascular mortality, and the risk
was 7-fold higher when ER was followed by the horizontal
ST-segment pattern (20). The highest risk (hazard ratio:
8.7, 95% confidence interval: 3.5 to 22) was observed for
persons with ER of the “notched” type followed by horizontal ST-segment (20). A third study retrospectively
analyzing a hospital database (in which 15% of patients had
established coronary artery disease) did not report the
Figure 3
Distribution of Patients With ER
Distribution of patients with early repolarization (ER) in our original case-control
series (comparing patients with idiopathic ventricular fibrillation [VF] to matched
controls and healthy athletes) (10) according to the morphology of their ST
segment (19). The predominant form of early repolarization in the idiopathic VF
group is the horizontal form (black bars); the predominant form in the 2 control
groups is the ascending form (gray bars), more so in the athletes’ group.
incidence of ER but did report the partition of the latter
into ascending versus horizontal (23). In this study, the
predominant form of ER (77%) was the rapidly ascending
pattern. Again, only ER with horizontal ST-segment
(present in 23% of patients with ER) was associated with
increased mortality (hazard ratio: 1.75) (23).
Given the age of the patients reported in these studies,
both at the time of inclusion and, more importantly, at the
time of survival curves divergencedsometime 20 years after
inclusion in the study (6)dwe speculated 2 years ago (1) that
adult patients with ER have an underlying increase in
dispersion of myocardial repolarization that places them at
higher risk for having VF during acute myocardial infarction
(MI). Several recent studies support that hypothesis (see
following text).
Early repolarization and coronary disease. Three recent
studies (24–26) suggest that patients who have ER are at
increased risk for having ischemic VF. First, Naruse et al. (24)
described 220 consecutive patients who presented with a first
MI and had a previous (pre-morbid) ECG for analysis. As
expected from previous studies (27), shorter duration of
symptoms and higher Killip class at presentation correlated
with higher risk for VF. However, the strongest independent
predictor of VF on multivariate analysis (odds ratio: 7) was an
ER pattern recorded before the ischemic event (24). The risk
was even greater when the pre-morbid ECG showed ER with
horizontal ST-segment in the inferior leads (odds ratio: 8;
95% confidence interval: 2 to 30). Conversely, ER with an
ascending ST-segment did not confer additional risk from
that predicted by clinical features (24). In the second study
(26), 30 patients with a first MI complicated by primary VF
were compared to 30 age- and sex-matched patients with
a first uncomplicated MI (26). On the ECG performed 5 days
after MI, ER was significantly more frequently observed
among the 30 VF cases compared with the 30 controls (14
[47%] vs. 4 [3%], p ¼ 0.05). All 14 patients with VF, and also
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Figure 4
Adler et al.
Malignant Form of Early Repolarization
JACC Vol. 62, No. 10, 2013
September 3, 2013:863–8
Incidence of ER
Incidence of early repolarization (ER) with rapidly ascending ST-segment (blue bars) and with horizontal ST segment (red bars) in different populations. The numbers in parentheses
represent the number of patients included in each study. *Only 107 of 151 ER-positive electrocardiograms (ECGs) were available for ST-segment morphology evaluation, and values
in the figure were estimated based on the available data. **Definition of ascending ST-segment was in accordance with the Tikkanen et al. (6) study (>0.1 mV elevation of the
ST-segment within 100 ms after the J point or a persistently elevated ST-segment of 0.1 mV throughout the ST-segment) for all studies in the figure except for Cappato et al. (>0.05
mV above baseline) (18) and Noseworthy et al. (visual analysis without cutoffs) (7). MI ¼ myocardial infarction; SCD ¼ sudden cardiac death; VF ¼ ventricular fibrillation.
3 of the 4 patients with uncomplicated infarction, had the
horizontal pattern (26). The third and largest study on this
issue compared 432 victims of out-of-hospital sudden death
(believed to be due to a fatal arrhythmogenic MI), with 532
patients with a nonfatal MI (25). Clinical correlates of a
fatal arrhythmic outcome were male sex, younger age, lower
body mass index, current smoking status, and nonuse of
beta-blockers and other cardiac medications, whereas a history
of prior angina or prior MI actually correlated with a nonfatal
outcome (25). The presence of ER on a pre-morbid ECG
strongly correlated with a fatal outcome even after adjusting
for gender and age (25). Specifically, the ER pattern with
a horizontal ST segment (but not with an ascending pattern)
was an independent predictor of sudden death (odds ratio:
2.15, 95% confidence interval: 1.20 to 3.85) (25).
The ER has also been linked to higher cardiac death and
arrhythmic death rates in vasospastic angina (28). Of 281
consecutive patients with documented vasospastic angina, 60
(21%) had ER during a remote ECG (recorded before or
long after the ischemic event). Subjects with ER and horizontal ST-segment had a higher age- and sex-adjusted risk
for cardiac events (mainly arrhythmic death) with a hazard
ratio of 8. In contrast, persons with the ascending type of
ER did not have an increased risk for arrhythmic events
during coronary spasm induced myocardial ischemia (28).
Idiopathic VF. We recently reviewed all published reports
that have ECG illustrations of idiopathic VF and found
89 ECG traces with ER. In accordance with our own
experience (see following text), in 70 (78%) of cases with
malignant ER, the ST-segment was horizontal (D. Viskin,
unpublished data).
In our own case-control series of idiopathic VF, ER
was more prevalent among patients with idiopathic VF
than among age- and sex-matched controls (42% vs. 13%,
p < 0.001) or among young athletes (42% vs. 22%,
p ¼ 0.013) (10). Moreover, while the horizontal pattern was
the predominant form in idiopathic VF (68% idiopathic VF
patients with J waves had an horizontal ST-segment), the vast
majority of healthy controls with ER had an ST-segment of
the rapidly ascending type, and this was particularly true for
the young athletes control group (Fig. 3) (19).
Two subsequent case-control studies comparing survivors
of unexplained cardiac arrest (presumed to have idiopathic
VF) to age- and sex-matched controls (21,29) support our
observations. In the first study, 5 (20%) of 25 cardiac arrest
survivors but only 2 (3%) of 60 controls, had ER with
horizontal ST-segment (p ¼ 0.02) (21). In fact, all the
patients with presumed idiopathic VF who had ER had the
horizontal pattern (21). The second study did not provide
data on ST-segment morphology for the control group but
did report that 9 of 10 cases with idiopathic VF and ER
demonstrated the horizontal ST-segment pattern (29).
The Emerging Story:
What Do We Know About Early Repolarization
Figure 4 demonstrates that the morphology of the STsegment in ER varies across the sudden death risk spectrum.
Adler et al.
Malignant Form of Early Repolarization
JACC Vol. 62, No. 10, 2013
September 3, 2013:863–8
The predominant ST-segment pattern gradually changes
from “ascending” (in blue) in the lowest risk group to
“horizontal” (in red) in the highest risk group.
Important limitations of the data presented in this figure
should be noted. First, the studies portrayed in Figure 4
differ greatly from each other by design and population
size, ranging from population-based studies of thousands of
patients to case-control series of <50 (Fig. 4). Second,
classification of the ST-segment is not always straightforward, mainly because the ST-segment may be horizontal in
some leads and ascending in others. In such cases, we have
adopted a “worst-case scenario” approach and have labeled
such ECGs as horizontal (19); however, this was an empiric
decision not necessarily followed by others. By definition (6),
a rapidly ascending ST-segment rises to >0.1 mV within
100 ms or remains elevated >0.1 mV throughout the STsegment; yet it remains to be defined if the prognostic
significance of this elevated but not ascending subtype is
comparable to that of the truly ascending type. Also, in some
patients, the ST-segment rises but at a slower rate. and it is
not clear how this slowly ascending ST segment type should
be classified. Conversely, idiopathic VF has been linked to
the congenital short QT syndrome (30) and patients with
symptomatic short QT often have ER (31). The combination of very short QT and ER will inevitably prevent a
horizontal ST segment despite a high risk for VF.
In all frankness, it is not at all clear whether the horizontal
pattern and the rapidly ascending pattern represent 2 truly
different forms of ER or whether they represent a continuum.
Above all, the heated debate between leading basic electrophysiologists (32) and authorities in clinical electrocardiography (33) concerning the true nature of ER is yet to be
resolved. Specifically, some argue that the premature and
heterogeneous repolarization of the action potential at
different myocardial levels, demonstrated clearly in the laboratory (32), is not necessarily the ECG feature long termed
“ER.” In this regard, it is important to focus on the patient
presented in Figures 1E and 1F. These traces (reproduced
from Ghosh et al. [34]) are from a cardiac arrest survivor with
a clinical diagnosis of malignant ER (9), who has the ECG
features of ER with horizontal ST-segment (best appreciated
in lead aVF in Fig. 1E) and also has intracardiac evidence of
premature repolarization recorded from the epicardial surface
with noninvasive electrocardiographic imaging (note the very
short activation-recovery intervals in nearby sites of normal
repolarization in Fig. 1F) (34).
Finally, the increased risk associated with the horizontal
pattern of ER demonstrated by Figure 4 should be put into
the proper perspective. It is of key importance that the terms
malignant and benign ER commonly used nowadays be
viewed as relative terms. In other words, although careful
analysis of the ST-segment morphology is useful for risk
stratification, the added value is generally not sufficient for
clinical decision making. For example, for the asymptomatic
patient with ER, an ascending ST-segment is certainly
reassuring but a horizontal form should not be interpreted as
867
a sign of high risk. As explained in detail elsewhere (19), the
risk of cardiac arrest due to idiopathic VF for an asymptomatic young adult with ER is only 1:3,000 even when
the ST-segment is horizontal. That is far lower than the
estimated VF risk in asymptomatic Brugada syndrome (z3%
at 3 years) (35), a condition for which the optimal management is ardently debated (36,37). Similar arguments can be
made for patients with syncope and no evidence of structural
heart disease. The vast majority of young patients in this
category have benign vagal syncope; only rarely, a syncopal
episode with malignant characteristics may raise concerns
about a condition predisposing to malignant ventricular
arrhythmias. In our series, as many as 32% of cardiac arrest
survivors with established idiopathic VF had the benign
rapidly ascending form (19). Thus, in a patient with ER
presenting with malignant syncope, a rapidly ascending STsegment cannot be automatically accepted as guaranty of an
excellent prognosis. The converse is also true: a horizontal
ST-segment in a patient presenting with typical vagal
syncope should not necessarily be interpreted as a malignant
sign. As a matter of fact, in a recent series of 160 patients
with suspected benign vagal syncope, 50 (31%) had ER. Of
these, the ST-segment pattern was horizontal in 8 (16%) and
ascending in 42 (84%) (38); thus 5% of all patients with vagal
syncope had horizontal ER (38). This is not surprising
considering that, in large series of unselected adults, the
predominant form of ER is actually the horizontal form
(Fig. 4).
Conclusions
Early repolarization has long been regarded as a benign
electrocardiographic phenomenon, literally, a sign of good
health. It was only 13 years ago when the suspicion that ER
might be proarrhythmic began to emerge from isolated case
reports (39) and pioneering experimental work (40).
Moreover, it has been only 5 years since the association
between ER and idiopathic VF was finally established by
case-control studies (9,10,41). The advances in our understanding of the pathophysiological (32) and genetic basis
(recently reviewed by Antzelevitch [42]) of ER during such
a short time frame have been remarkable. It is now clear that
the morphology of the ST segment, within the frame
context of ER, provides important diagnostic and prognostic
information. This information, however, needs to be viewed
in the proper perspective.
Reprint requests and correspondence: Dr. Sami Viskin,
Department of Cardiology, Tel Aviv Medical Center, Weizman 6,
Tel Aviv 64239, Israel. E-mail: [email protected].
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Key Words: athletes
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early repolarization
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ventricular fibrillation.