The early repolarization syndrome.
- PubMed: 2745947
The syndrome of the early repolarization variant is described. This benign ECG phenomenon is noted in 1% to 2% of the adult population and generally occurs in the absence of myocardial disease. The ECG manifestations may mimic acute myocardial injury or pericarditis. Exercise and isoproterenol tend to normalize the RST segment elevation. The presence of "early repolarization" does not preclude diagnosis of exercise-induced myocardial ischemia by treadmill testing, and coronary vaso-occlusive lesions may be demonstrated in some patients with the early repolarization pattern on ECG. The presence of S-T elevation in a patient with chest pain of possible cardiac origin mandates hospitalization and cardiac monitoring even if the ECG may confirm to a classic pattern of early repolarization; in this context, the diagnosis of benign early repolarization is one of exclusion. Recognition of this clinical entity and the use of previous ECGs for comparison would in most cases forestall the administration of thrombolytic agents to patients with S-T segment elevation due to benign early repolarization.
The early repolarization syndrome. -
Official Journal of the Japanese Circulation Society
udden cardiac death (SCD) is defined as an unexpected
natural death from a cardiac cause within a short time
period, generally ≤1 h from the onset of symptoms, in
a person without any prior condition that would appear to
result in instantaneous fatality.1 The majority of SCD events
are associated with structurally diseased heart. Ventricular
tachycardia (VT) degenerating first to ventricular fibrillation
(VF) and later to asystole appears to be the most common
pathophysiological cascade involved in fatal arrhythmias
recorded as the primary electrical event at the time of SCD,
particularly in patients with advanced heart disease. In pa-
tients without structural heart disease, polymorphic VT and
torsades de pointes caused by various genetic or acquired
cardiac abnormalities, such as ion-channel abnormalities,
or acquired long-QT syndrome commonly contribute to the
initiation of life-threatening arrhythmias.1 Primary electro-
physiological disorders with known (long QT syndrome,
Brugada syndrome, catecholaminergic polymorphic VT, short
QT syndrome) or unknown (early repolarization (ER) syn-
drome, idiopathic VF) ion-channel abnormalities are respon-
sible for 10% of SCDs.2–8
For decades, ER, which is characterized by an elevation
of the junction between the end of the QRS complex and the
beginning of the ST segment (ie, the J point) from baseline
on standard 12-lead electrocardiogram (ECG), has been
considered to be benign ECG manifestation.9–15 However the
presence of this pattern, especially in the inferior or lateral
leads, has recently been recognized in some studies as associ-
ated with vulnerability to VF.8,16,17 This review summarizes
our current state of knowledge of ER syndrome.
Electrocardiogram of Early Repolarization
Definition of Early Repolarization
The ER pattern is a common electrocardiographic variant
characterized by J-point elevation manifested either as QRS
slurring (at the transition from the QRS segment to the ST
segment) or notching (a positive deflection inscribed on ter-
minal S wave), ST-segment elevation with upper concavity
and prominent T waves in at least 2 contiguous leads.7,8,17,18
In most of the studies elevation of the J point and/or ST-
segment from the baseline by at least 0.1 mV was considered
definitive of ER (Figure).3,8
Diagnosis of Early Repolarization Syndrome Associated
With Idiopathic VF
To evaluate the association between ER and idiopathic VF,
patients with other known diseases have to be distinguished
from patients with idiopathic VF. On the basis of published
guidelines, patients are classified as having idiopathic VF
if they have no identifiable structural heart disease demon-
strated by echocardiographic biventricular dimensions and
function, no detectable coronary artery disease on coronary
angiography or exercise testing, and no known repolariza-
tion abnormalities.1,19 Secondly, cases of primary electrical
disorders should be excluded if the QT interval corrected for
heart rate (QTc) is less than 340 ms (short QT interval) or
more than 440 ms (long QT interval) at baseline and before
arrhythmia.2,3 Patients with the Brugada syndrome, defined
as right bundle branch block and ST-segment elevation
(≥0.2 mV) in ≥2 precordial leads V1–3, without intervention
or following infusion of a sodium-channel blocker,4 should
also be excluded. In addition, patients with catecholaminergic
arrhythmias, defined as arrhythmias during catecholamine
Received August 22, 2010; accepted August 24, 2010; released online September 11, 2010
Hôpital Cardiologique du Haut-Lévêque and the Université Victor Segalen Bordeaux II, Bordeaux-Pessac, France
Mailing address: Shinsuke Miyazaki, MD, Hôpital Haut-Lévêque, 33604 Bordeaux-Pessac, France. E-mail: firstname.lastname@example.org
ISSN-1346-9843 doi: 10.1253/circj.CJ-10-0753
All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: email@example.com
Early Repolarization Syndrome
– A New Electrical Disorder Associated
With Sudden Cardiac Death –
Shinsuke Miyazaki, MD; Ashok J Shah, MD; Michel Haïssaguerre, MD
Early repolarization (ER), consisting of a J-point elevation, notching or slurring of the terminal portion of the
R wave (J wave), and tall/symmetric T wave, is a common finding on the 12-lead electrocardiogram. For decades,
it has been considered as benign, barring sporadic case reports and basic electrophysiology research that sug-
gested a critical role of the J wave in the pathogenesis of idiopathic ventricular fibrillation (VF). In 2007–2008, a
high prevalence of ER in patients with idiopathic VF was reported and subsequent studies reinforced the results.
This review summarizes the current state of knowledge concerning ER syndrome associated with sudden cardiac
death. (Circ J 2010; 74: 2039 – 2044)
Key Words: Early repolarization; Idiopathic ventricular fibrillation; J wave; Sudden cardiac death
2040 MIYAZAKI S et al.
infusion or exercise testing, should be excluded. To avoid
confusion with the pattern commonly seen in highly trained
athletes (J-point elevation + ST elevation in V2–4), the term
“inferolateral J wave elevation syndrome” is probably more
appropriate for the ER associated with VF.
Prevalence in the General Population and in Patients
With Idiopathic VF
The prevalence of ER in the general population varies from
less than 1% to 13%, depending on age (predominant in young
adults), race (highest among black populations), sex (pre-
dominant in males), and the criterion for J-point elevation
(0.05 mV vs 0.1 mV).7,8,17,18,20,21 The most comprehensive
study to date evaluating the prevalence and prognostic sig-
nificance of ER in a community-based general population of
10,864 middle-aged subjects reported the prevalence of ER
as 5.8% (5.0% in the control group studied in our report8),
including 3.5% in the inferior leads, 2.4% in the lateral leads,
and 0.1% in both, using the same ECG criteria.17 With J-point
elevation ≥0.2 mV, the prevalence dropped to 0.33% (0.7%
in the control group studied in our report8).17
In patients with documented idiopathic VF and a structur-
ally normal heart, the prevalence of ER was 31%.8 Prevalence
rates up to 60% have been reported in smaller studies.22 The
prevalence of the ER pattern with J-wave elevation ≥0.2 mV
in patients with idiopathic VF was found to be 16%.8
History of Early Repolarization
Early Repolarization in the Past
The J-point deflection occurring at the QRS-ST junction (also
known as the Osborn wave or J wave) was first described by
Tomaszewski in 1938.23 An ER pattern that was slurring or
notching of the terminal part of QRS complex on the ECG
was first described in 1936.24 However, it was a wide- and
long-held belief that ER on ECG was not associated with
any adversity. This long-held concept was reconsolidated
by Klatsky et al in 2003 in a study involving 73,088 patients
who underwent voluntary health examination, including ECG,
in Oakland, California, between 1983 and 1985.15 The authors
concluded that the prevalence of ER in their cohort was 0.9%
(670/73,088) and that the patients with ER were less likely to
experience arrhythmias. The overall rate of hospitalization
and outpatient visits was not higher than in the control popu-
Early Repolarization in the Current Era
During the past decade, a number of clinical reports (mostly
from Japan) have described patients who had sudden cardiac
arrest associated with abnormal J waves; however, ER was
reported as the only “abnormal” finding in patients diagnosed
with idiopathic VF.25–38 Meanwhile, the potential arrhyth-
mogenicity of ER was also demonstrated in experimental
studies.39–42 These observations pointed towards a potentially
non-benign nature of ER. More definitive clinical evidence
and a turning point in our perception of ER came in 2007–
2008 when we reported a high prevalence of ER in patients
Figure. J-wave elevation (arrow) as slurring (A) or notching (B) in the inferior or lateral electrocardiogram leads in patients with
2041Early Repolarization and Sudden Cardiac Death
with idiopathic VF.8,43 ER was observed in 31% (64/206) of
idiopathic VF cases vs 5% (21/412) of well-matched healthy
subjects (P<0.001). Furthermore, based on data from implant-
able cardioverter-defibrillators (ICD), 64 idiopathic VF sur-
vivors with ER experienced higher VF recurrence than 142
VF survivors without ER (41% vs 23%, P=0.008). Sub-
sequently, Rosso et al compared the ECGs of 45 idiopathic
VF cases with those of 124 age- and sex-matched control
subjects and 121 young athletes and found that ER was more
common among the patients with VF than among the control
subjects (42% vs 13%, P=0.001).16 This was particularly true
for J-point elevation in the inferior leads (27% vs 8%, P=
0.006) and was true for J-point elevation in leads I to aVL
(13% vs 1%, P=0.009). In contrast, J-point elevation in V4–6
occurred with equal frequency among patients and matched-
control subjects (6.7% vs 7.3%, P=0.86). In another study by
Nam et al, baseline ECGs of 11 of 19 (57.9%) patients with
VF showed ER in contrast to 3.3% of 1,395 controls repre-
senting the general population.20
Although case – control studies do not establish causation,
strong evidence in favor of an association between ER and
VF-related SCD has emerged. Tikkanen et al systemically
reported the long-term outcome of ER in the general popula-
tion.17 The authors assessed the prevalence and prognostic
significance of ER on routine ECG performed during a com-
munity-based investigational study of coronary artery disease
among 10,864 middle-aged subjects. The mean follow-up was
30±11 years with the primary endpoint of cardiac death and
secondary endpoints of all-cause mortality and arrhythmic
death. The prevalence of ER was 5.8% in this cohort. Impor-
tantly, ER in the inferior leads was found to be associated
with an increased risk of cardiac death (adjusted relative risk,
1.28; 95% confidence interval (CI), 1.04 to 1.59, P=0.03) in
their general population. J-point elevation in the lateral leads
was of borderline significance in predicting cardiac death
and all-cause death. Moreover, the survival curves started to
diverge 15 years after the first ECG recording in the early
1980s and continued to diverge at a constant rate throughout
the follow-up period, despite continued improvement in the
treatment and prognosis of patients with cardiac disease dur-
ing the past 2 decades. Although the authors retrospectively
classified cardiac deaths into arrhythmic and non-arrhythmic
categories, the results strongly challenge the long-held benig-
nancy of ER. On the other hand, 59 of 630 subjects with ER
in the general population died of a proven arrhythmic cause
over a mean period of 30±11 years. Considering these data,
the prevalence of so-called malignant ER turns out to be
1 per 10 cases of the ER pattern on ECG, proving that 9 of
10 cases of ER on ECG really should have been benign. Also,
the multivariate adjusted risk of all-cause mortality asso-
ciated with the presence of ER in any lead or magnitude was
Mechanisms of Early Repolarization
The exact mechanism for ER is still unknown. In 1991,
Antzelevitch et al first proposed transmural differences in the
early phases of the cardiac action potential (phases 1 and 2)
as probably responsible for inscription of the ECG J wave.44
Subsequently, they obtained direct evidence in support of this
hypothesis in arterially perfused canine ventricular wedge
preparations in 1996.45 Briefly, an arrhythmogenic platform
is created by disproportionate amplification of the repolariz-
ing current in the epicardial myocardium due to a decrease
in the inward sodium or calcium channel currents or an
increase in the outward potassium currents mediated by the
Ito, IK-ATP, IK-Ach channels. The trigger and substrate for devel-
opment of phase 2 reentry and VT/VF eventually emerge
from the transmural dispersion in the duration of cardiac
Because ER was not associated with an increased risk of SCD
until recently, the genetic markers to differentiate benign
and arrhythmic forms of ER have not been identified. The
importance of the genetic background in ER has recently
been suggested by our report,8 which showed that 16% of
cases with VF and ER have a family history of SCD. Given
the high frequency of the genetic background underlying the
ER pattern in the population, it is probably polygenic and
influenced by environmental factors.
As described previously, rare monogenic forms of ER
have been reported using a candidate gene approach. ER on
ECG suggests a shift in transmural voltage gradient between
the epicardium and endocardium as a causal mechanism. An
increase in the Ito, IKr, IKs, IKACH, IKATP current or a decrease
of the sodium INa and/or calcium ICaL current could lead to
this phenomenon. Recently, we identified the first genetic
abnormality associated with idiopathic VF and inferolateral
ER, which was a rare variant in KCNJ8,46 responsible for
the pore-forming subunit Kir6.1 of the IKATP channel, using
a candidate gene approach in a 14-year-old girl who was
resuscitated following an episode of sudden death caused by
VF with ER More recently, Medeiros-Domingo et al investi-
gated 101 patients with J-wave syndromes, including 87 cases
of Brugada syndrome and 14 of ER syndrome, and 1 case in
each group hosted the identical missense mutation, KCNJ8-
S422L.47 It was supported by the finding that KCNJ8 is a
novel J-wave syndrome-susceptibility gene. Burashnikov et al
identified a missense variant in the β2 subunit of the cardiac
L-type calcium channel in patients with the ER syndrome.
Expression studies for this variant are not available as yet.48
Early Repolarization or Delayed Depolarization?
Although the J wave is synonymously used with the ER ab-
normality, the mechanistic evidence elucidating the inscrip-
tion of the J wave on the surface ECG is incomplete. Basic
investigators propose the inscription of J wave as coincident
with phase 1 of the cardiac action potential in the epicardial
region of the ventricular myocardium, which precedes phase
1 in the endo- and mid-myocardial cells, generating an early
gradient in the repolarization currents within the ventricles,
thereby justifying the J wave as an ER phenomenon.44,45 In
accordance with that, some clinical investigators have con-
cluded that the J wave should be considered as a repolariza-
tion phenomenon, rather than as late depolarization, because
of its slower inscription, spontaneous/rate dependant fluctua-
tion in a morphologic pattern (increased pattern at slow heart
rate, decreased pattern at faster heart rate) or amplitude in the
face of stable QRS complexes, and amplitude varying concur-
rently with the ST segment. These investigators did not find
late potentials (LPs) on high-amplification ECG and invasive
endocardial mapping further reinforced their view.8 Recently
Abe et al analyzed 22 idiopathic VF patients using a newly
developed signal-averaging system to record LPs (depolar-
ization marker), T-wave alternans (TWA) and QT dispersion
(QTD) (repolarization markers).49 J waves were significantly
associated with all LP parameters, but TWA and QTD were
not. They concluded these finding might support the idea that
2042 MIYAZAKI S et al.
J waves are more strongly associated with a depolarization
abnormality than with a repolarization abnormality.
Risk Stratification of VF
As described earlier, although ER is a common entity, unex-
plained SCD in young adults is very rare. Rosso et al claimed
that the presence of a J wave on the ECG of a young adult
would increase the probability of VF from 3.4:100,000 to
11:100,000, which is a negligible rise.16 They, therefore,
concluded that the incidental discovery of a J wave on rou-
tine screening should not be interpreted as a marker of “high
risk” for sudden death, because the odds for this fatal disease
would still be approximately 1:10,000.16 However, needless
to say careful attention should be paid to subjects with “high
In such a situation, we consider that close follow-up should
be offered to patients with ER and a history of unexplained
syncope or a family history of unexplained sudden death.
Abe et al reported that the prevalence of ER in 222 patients
with syncope and no organic disorder was 18.5%, which is
almost 10-fold that in 3,915 healthy controls (2%).50 There-
fore, the possibility of ER-associated syncopal episodes can-
not be excluded in at least some of these patients. The genetic
basis of ER is still largely unknown. Also, in patients with
VF and ER, a positive family history of sudden death was not
significantly higher than in those without ER (16% vs 9%,
P=0.17).8 Nevertheless, it does not imply that family history
is not an important aspect of the background to ER patients.
Magnitude of the J Wave
We also founded that the magnitude of the J-wave elevation
in the case group was significantly higher than that in the
control subjects (2.0±0.8 mV vs 1.2±0.4 mV, P<0.001).8 In
the study by Tikkanen et al, subjects with J-point elevation
>0.2 mV on inferior leads not only bore a higher risk of death
from cardiac causes (adjusted relative risk, 2.98; 95%CI,
1.85–4.92, P<0.001) as compared with a J-point elevation
>0.1 mV, but also had a markedly elevated risk of death from
arrhythmia (adjusted relative risk, 2.92; 95%CI, 1.45–5.89,
P=0.01).17 This finding indicates that the magnitude of the
J-point elevation could be a discriminator of risk. It is wor-
thy to note that a J-point elevation >0.2 mV seems to be rare
in the normal population. Three-quarters of the subjects with
a J-point elevation on baseline measurement had the same
pattern several years later.17 However, it is necessary to point
out that the magnitude of the J-wave elevation can fluctuate,
even without drug provocation or exercise, which means that
a low-magnitude J wave should not be considered as a static
We performed serial ECGs during electrical storm (includ-
ing frequent ventricular ectopy and episodes of VF) in 18
subjects and all showed a consistent and marked increase in
the amplitude of the J wave during the period of storm when
compared with the baseline pattern (from 2.6±1 mm to 4.1±
2 mm, P<0.001).8 Besides spontaneous accentuation of the
J-wave amplitude preceding the electrical storm, spontane-
ous beat-to-beat fluctuation in the morphologic pattern of
ER was also observed.8 Nam et al investigated the initiation
of VF episodes and reported a dramatic, but very transient,
accentuation of J waves prior to the development of elec-
trical storm in 5 patients.20 The available data suggest that
transient J wave augmentation portends a high risk for VF in
patients with ER.
Distribution of the J Wave
In normal subjects, most of the ER is confined to the inferior
leads, lateral leads or left precordial leads. As reported by
Tikkanen et al, of 630 subjects with ER, only 16 (2.5%) had
ER in both the inferior and lateral leads.17 Focusing on pa-
tients with VF, we found that 46.9% of patients with VF and
ER showed the ER pattern in both inferior and lateral leads.8
Similarly, the global presence of ER was observed in none
of the 46 subjects with ER without VF (selected from among
1,395 individuals from the general population), but was in
45.5% of patients with ER who developed VF.20 The impli-
cations of a global J wave are unknown, but, theoretically,
this characteristic obviously means a much more diffuse
Morphology of the J Wave
Recently, Merchant et al compared the baseline ECGs of
9 patients with VF/VT and ER (so-called malignant ER) and
61 age- and sex-matched controls with normal ER (so-called
benign ER).52 The results demonstrated that QRS notching
was more prevalent among cases than controls in leads V4
(44% vs 5%, P=0.001), V5 (44% vs 8%, P=0.006) and V6
(33% vs 5%, P=0.013). They concluded that left precordial
terminal QRS notching is more prevalent in malignant vari-
ants of ER than in benign cases and could be used as a tool
for risk stratification of subjects with ER. However, the case
number in that study was small and included 3 patients with
idiopathic monomorphic VT without VF.52
Correlation Between J-Point Location and Origin
We presented a definitive association between ER and idio-
pathic VF by mapping the ventricular ectopy initiating the VF
in patients with ER and idiopathic VF.8 In 6 patients with
ER recorded in inferior leads alone, all cases of ectopy origi-
nated from the inferior left ventricular wall. In the subjects
with widespread global ER, as recorded in both inferior and
lateral leads, ectopy originated from multiple regions.8,53
These findings prove that the ER abnormality may be either
limited to a single region in the ventricles or can extend
beyond to involve more than 1 region simultaneously. The
link between this ECG pattern and malignant arrhythmias is
supported by both the accentuated repolarization before the
onset of arrhythmia in the case subjects and the origin of
triggering beats from the region of ER. For patients who are
diagnosed with idiopathic ventricular arrhythmias and ER, an
alarm should be raised if the origin of arrhythmia, as identi-
fied by the morphology of VF-initiating ventricular ectopy,
is concordant with the location of ER.
LPs by a Signal-Averaged System Using 24-h Holter
Abe et al reported that patients with idiopathic VF and
J waves had a high incidence of LPs showing a circadian
variation with night ascendancy.49 TWA and QTD were not
useful, but detection of LPs by a signal-averaged system
using 24-h Holter electrogram was a useful technique for
identifying those at high risk for arrhythmic events.
Invasive Induction of VF
Induction of VF was attempted in 132 VF patients from 2 dif-
2043Early Repolarization and Sudden Cardiac Death
ferent ventricular sites and up to 3 extrastimuli.8 The patients
with ER did not show significantly higher inducibility than
those without ER.8 Moreover, a low rate of VF inducibility
(34%) in the patients with a clinical history of VF makes the
electrophysiologic study less sensitive for risk stratification
of symptomatic patients.
Management of VF Associated With
Management of Electrical Storm During the Acute Phase
We reported the effect of drug therapy for electrical storm in
patients with ER and idiopathic VF in a multicenter study.51
Of 122 patients with VF and ER, 33 (27%) experienced more
than 3 episodes of VF and 16 experienced electrical storm
(≥3 VF/24 h). In this population, electrical storm was unre-
sponsive to β-blockers, lidocaine/mexiletine, and verapamil,
but amiodarone was partially effective. In contrast, isoproter-
enol infusion immediately suppressed electrical storm. Acute
control of arrhythmia could be achieved by deep sedation
and/or isoproterenol infusion.8,51
Management of Recurrent VF During the Chronic Phase
Patients with VF and ER have shown a higher incidence of
VF recurrence than VF patients without ER (43% vs 23%,
P<0.001) during 5 years of follow-up.8 We reported that dur-
ing follow-up of 69±58 months, oral antiarrhythmic drugs
were poorly effective in preventing recurrent VF: β-blockers,
verapamil, mexiletine, amiodarone, and class 1C antiarrhyth-
mic drugs.51 However, quinidine was effective in 9 of 9 pa-
tients, decreasing recurrent VF from 33±35 episodes to nil for
25±18 months of follow-up.8,51 Interestingly, the ER pattern
was closely linked to the period of occurrence of arrhythmia
and was helpful in monitoring the efficacy of drug therapy.
At the time of arrhythmia occurrence, ER was more pro-
nounced than during the period without arrhythmia.
Other Therapeutic Options
Based on these observations, patients with VF and ER may
be candidates for treatment over and above an ICD. To
weather an electrical storm that is resistant to antiarrhythmic
drugs, left ventricular assistance and cardiac transplantation
may be required.
Catheter ablation of the ectopy initiating the VF could be
another potential modality for the management of VF pa-
tients with ER who fail to respond to drugs. Catheter ablation
eliminated all ectopies in 5 of 8 subjects; however, there were
no data during long-term follow-up and further studies are
Current scientific evidence drawn from a large cohort of sub-
jects with long-term follow-up suggests that ER, particularly
if recorded in the infero-lateral leads, is not always as benign
as traditionally thought. There is a high prevalence of ER in
the patients experiencing first, recurrent and stormy episodes
of idiopathic VF. We necessarily recommend careful eval-
uation of patients with ER in association with unexplained
syncope, a family history of SCD or idiopathic ventricular
arrhythmias. It is equally important to prospectively inves-
tigate the prognostic value of a J wave >0.2 mV, a global
J wave and a notched J wave in the left precordial leads. For
patients with recurrent VF, isoproterenol in acute cases and
quinidine in chronic cases are effective antiarrhythmic drugs.
Future clinical and experimental studies should focus on
understanding the exact mechanisms and reasons for this
pattern, on establishing the method of risk stratification and
ultimately on devising strategies to prevent premature death
from cardiac causes in subjects with this pattern.
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