Clinical and Mechanistic Issues in Early Repolarization: Of Normal Variants

and Lethal Arrhythmia Syndromes

Begoa Benito, Eduard Guasch, Lena Rivard, and Stanley Nattel
J. Am. Coll. Cardiol. 2010;56;1177-1186
doi:10.1016/j.jacc.2010.05.037
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Journal of the American College of Cardiology

2010 by the American College of Cardiology Foundation
Published by Elsevier Inc.

Vol. 56, No. 15, 2010

ISSN 0735-1097/$36.00
doi:10.1016/j.jacc.2010.05.037

STATE-OF-THE-ART PAPER

Clinical and Mechanistic

Issues in Early Repolarization
Of Normal Variants and Lethal Arrhythmia Syndromes
Begoa Benito, MD, Eduard Guasch, MD, Lena Rivard, MD, Stanley Nattel, MD
Montreal, Quebec, Canada
Early repolarization, involving ST-segment elevation and, sometimes, prominent J waves at the QRS-ST junction,
has been considered a normal electrocardiographic variant for over 60 years. A growing number of case reports
and case-control studies indicate that in some instances, early repolarization patterns are associated with
increased risk of idiopathic ventricular fibrillation. Epidemiological evidence indicates a dose effect for the risk of
cardiac and sudden death with the extent of J-point elevation. This paper reviews present knowledge regarding
the epidemiology, presentation, therapeutic response, and mechanisms characteristic of early repolarization. We
highlight major unanswered questions relating to our limited ability to determine which individuals with this
common electrocardiographic variant are at risk for sudden death, our incomplete understanding of underlying
mechanisms, the inadequate information regarding genetic determinants and therapeutic responses, and the
unclear relationship between early repolarization and other conditions involving accelerated repolarization and
sudden arrhythmic death such as Brugada and short-QT syndromes. This review paper intends to inform the
practicing physician about important clinical issues and to stimulate investigators to address the many unresolved questions in this rapidly evolving field. (J Am Coll Cardiol 2010;56:117786) 2010 by the American
College of Cardiology Foundation

Sudden cardiac death (SCD) is a major contributor to

population mortality. The most common cause of SCD is
ventricular fibrillation (VF). Sudden cardiac death involves
coronary artery disease and its complications in up to 60% to
80% of cases, followed by other cardiomyopathies (1,2).
However, in 10% to 20% of SCDs (30,000 to 60,000 deaths
annually in the U.S.), no structural abnormalities are detectable (3). Many of these are caused by primary electrical
disorders, including long-QT syndrome (4), catecholaminergic polymorphic ventricular tachycardia (5), short-coupled
torsades de pointes (6), Brugada syndrome (BrS) (7), and
the short-QT syndrome (SQTS) (8), as well as cases
identified as idiopathic VF (IVF) when no specific etiology is known. These unexpected deaths represent a tremendous burden to families, community, and health care
providers.
For over 60 years, ST-segment elevation in the absence of
conduction abnormalities or chest pain, occurring particu-

larly in young, bradycardic individuals, has been considered

a normal variant called early repolarization (ER) (9). As
recently as 7 years ago, an analysis of over 2,000 patients
followed for 12 years, of whom 670 had ER, confirmed a
benign outcome and a reduced arrhythmia burden (10).
However, a series of case reports (1115), culminating in
more recent larger-scale studies (16 18), suggest a more
worrisome picture, with clear over-representation of individuals with ER patterns in IVF populations. Early repolarization is present in 5% of the population (16,18), so its
potential arrhythmic significance is very challenging. How
should the physician advise a patient with this electrocardiographic variant that was until recently considered normal? How can ER-related SCD be predicted and prevented? What are the basic mechanisms underlying ER and
associated arrhythmias? In this paper, we review the available information, focusing on possible mechanisms, clinical
features, and management issues, and highlight important
unanswered questions.

From the Research Center and Department of Medicine, Montreal Heart Institute
and Universit de Montral, Montreal, Quebec, Canada. Supported by Canadian
Institutes of Health Research (MOP 68929), Leducq Foundation (07/CVD/03), Plan
Nacional de Investigacion Cientfica, Desarrollo e Innovacion Tecnologica, Instituto
de Salud Carlos III/FIS (CM06/00189 and CM08/00201), and Fundacion Alfonso
Martn Escudero. The authors have reported that they have no other individual
relationships to disclose. Drs. Benito and Guasch contributed equally to this paper.
Manuscript received February 26, 2010; revised manuscript received May 20, 2010,
accepted May 25, 2010.

Historical Background
The ER pattern is defined by ST-segment elevation, often
accompanied by slurring or notching on the terminal QRS,
called a J-wave (Figs. 1A and 1B). This pattern was first
described as a normal variant by Shipley and Hallaran in
1936 (19). Reports in the 1950s and 1960s confirmed with

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increasing sample sizes the benign nature of what was also

called normal RS-T segment elAP action potential
evation variant, or juvenile ST
BrS Brugada syndrome
pattern, and defined characterECG electrocardiogram
istic features such as predomiER early repolarization
nance among male, black, young,
ICD implantable
and physically active individuals
cardioverter-defibrillator
and regression of electrocardioIto transient outward
graphic changes during exercise
current
(20,21).
IVF idiopathic ventricular
After an initial report in 1984
fibrillation
(11), a growing number of case
SCD sudden cardiac
reports in the late 1990s dedeath
scribed an association between
SQTS short-QT syndrome
ER patterns and IVF (1215)
VF ventricular fibrillation
and a potential basic mechanism
was suggested (22). In a large
case-control study (16), ER was 6 times more common in
206 IVF patients than in 412 matched controls, and IVF
subjects with ER were at increased risk of recurrent SCD. A
very recent study of over 10,000 unselected subjects followed
for 30 years found that ER patterns are associated with
increased cardiac and arrhythmic mortality: 2-mV inferior
ST-segment elevation conferred a 3-fold risk increase for
cardiac mortality and SCD (18).
Abbreviations
and Acronyms

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precordial leads, a pattern thought to entail more benign

outcomes. Blacks appear particularly predisposed to ER
(10,20,28). Paradoxically, blacks have been underrepresented in studies assessing malignant ER, and the
arrhythmic risk of ER among blacks is undetermined. The
inter-relations among epidemiological factors predisposing
to ER are also uncertain. For example, it is unknown
whether the roles of young age, male sex, physical activity,
and racial predilection are related to common underlying
factors such as vagal tone and slow heart rate, or whether
each contributes independently. The relationships between
risk factors for ER per se and SCD-associated ER are also
unclear, although male sex clearly appears to be preponderant in both.
Genetic contributions to SCD-associated ER are suggested by common familial SCD histories (16,26) in
symptomatic ER patients. Geographic differences in
distribution have also been described, with ER-related
SCD being particularly prevalent among South-East
Asians (11,13,29).

Epidemiological Aspects
Early repolarization occurs in 1% to 9% of the general
population (10,16,18), and in 15% to 70% of IVF cases
(16,17,2325). Based on such series, ER is considered to
convey a 4- to 10-fold SCD risk increase (16,25). In the
35 to 45 year age range of maximal ER-related SCD
incidence (16,24,26), a J-wave is estimated to increase
IVF risk from 3.4 per 100,000 to 11 per 100,000 (25).
However, estimates based on index series of IVF cases
may not be applicable to asymptomatic individuals with
ER. In a longitudinal survey of 10,864 asymptomatic
individuals (age at recruitment 44 8 years, follow-up
30 11 years), arrhythmic death risk increased 1.4-fold
with 0.1-mV and 2.9-fold with 0.2-mV J-point
elevation in the inferior leads (18).
Male sex is strongly associated with ER: over 75% of
individuals with ER are men. Men present greater J-point
elevation than women do (18,25) and represent 75% of
malignant cases (16,17). Male predominance may result
from larger epicardial transient outward current (Ito) density
versus Ito in women (27), although the detailed sex-related
ion-channel expression profile remains to be established.
The ER pattern is more common in younger physically
active individuals (10,18) and may regress with aging
(20,28). Estimates of the prevalence in trained individuals
range from 20% in noncompetitive athletes to 90% in elite
athletes. In this population, ER often appears in mid

Figure 1

Electrocardiographic Pattern of Early Repolarization

Characteristic early repolarization electrocardiographic pattern, described as a

normal variant in the 1960s (A) (adapted, with permission, from Wasserburger
and It [21]), and more recently associated with idiopathic ventricular fibrillation
(B) (adapted, with permission, from Takagi et al. [14]).

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Electrocardiographic Features and Modulators

Pharmacological Responses

The J-point marks ST-segment onset. The degree of

J-point elevation determines SCD risk (18) and increases in
J-wave amplitude often precede VF episodes (16,17). Other
J-wave properties may also carry prognostic information
(25). A small study of 9 malignant ER patients (with SCD
history) and 200 benign ER subjects suggested an association of malignant ER with terminal-QRS notching
versus slurring in left precordial leads (V4 to V5) (24). This
has not been confirmed for ER affecting inferior leads,
where the degree of J-point elevation appears to be the only
risk predictor (18).
Localization of the ER pattern could have prognostic
implications. Case-control studies have associated aborted
SCD with ER in inferior and, less commonly, lateral leads
(16,26,30). Conversely, in asymptomatic individuals, ER is
most prominent in midprecordial leads (V2 to V4) (28), a
pattern that is especially predominant among athletes and is
believed to carry a benign prognosis. Early repolarization in
inferior leads was the sole location clearly associated with an
increased arrhythmic-death risk in the only large-scale
longitudinal cohort study available (18). Combined inferiorand lateral-lead ER occurred in 16 cases, slightly greater
than the 10 predicted based on independence of location. In
the Haissaguerre et al. (16) case-control study, IVFassociated ER manifested in inferior leads in 28, in lateral
leads in 6, and both in 30 cases.
Premature beats triggering VF can be localized to regions
showing ER and ablation of such zones can prevent IVF
recurrence (16). Accordingly, it has been suggested that
when multiple regions are affected on an electrocardiogram
(ECG), different ventricular ectopic complex morphologies
occur and arrhythmic risk increases (16,30).
There is no clear QT-interval difference between individuals with ER and controls (18), reinforcing the notion
that the acceleration of repolarization in ER is local.
Signal-averaged electrocardiographic late potentials reflecting conduction abnormalities are seen in 10% of IVF
patients with ER (16,17), confirming that ER is primarily a
repolarization disorder.
The ER pattern is labile: autonomic tone and heart rate
likely play major roles in ER variability. The ER-associated
IVF events are more likely to occur in vagal contexts such as
sleeping or after meals (1316,26) and J-point amplitude
increases at night (26). Conversely, adrenergic stimulation
suppresses ER and associated arrhythmic events (30).
Whether autonomic influences are mediated exclusively
via heart-rate change or by direct actions on ion currents
is unclear. It has been suggested that time-dependent
recovery of Ito from inactivation could explain decreased
J-wave amplitude with increased heart rate (27). Temperature can also modulate J waves and ST-segment
elevation; hypothermia classically induces prominent
J waves (Osborn waves) (31).

Various pharmacological responses have been described

clinically, but data from controlled trials or experimental
studies are largely lacking. Preliminary clinical experience
with quinidine is promising (12,32). Beta-adrenergic agonists are beneficial in IVF (30,32,33), particularly for arrhythmic storm. Amiodarone has been reported effective in
some patients (13), but its overall efficacy is limited (32).
Several studies suggest that Na-channel blockers such as
ajmaline do not modify ER (15,17,32) or accentuate it
slightly (12,14), in contrast to the worsening typically seen
in BrS.
Patient Management
No controlled studies of ER management have been published, and recommendations are based on small series and
case reports.
Secondary prevention. For ER patients resuscitated from
IVF, implantable cardioverter-defibrillator (ICD) implantation is required unless contraindications apply (34). In
patients with ICDs and frequent nonsustained ventricular
tachyarrhythmias and/or ICD shocks, adjuvant antiarrhythmic therapy with quinidine may be helpful (17,32). No
information is available about lifestyle modification, but it
may be prudent to advise highly active patients with resting
bradycardia and malignant ER to reduce physical-training
programs.
Arrhythmic storm occurs in about 10% of patients with
ER-related SCD (32). Isoproterenol infusion, titrated to
increase heart rate beyond 90 and up to 120 beats/min,
suppresses arrhythmic events (30,32,35), as do other heart
rate-increasing interventions (such as atrial or ventricular
pacing) (30,32). In patients refractory to standard therapy,
endocardial ablation of ectopic sources in the ER zone can
be useful (16).
Primary prevention. Primary prevention of SCD in
asymptomatic ER presents a major challenge. Few reliable
criteria are available to stratify SCD risk. Inferior J-point
elevation 2 mm predicts a 3-fold increase in SCD risk
(18). However, even this high-risk group does not diverge
from the control population until at least 10 years after the
index electrocardiogram (18), so any intervention must be
very safe, in addition to effective. Some ECG features
reflecting cardiac repolarization such as T-wave alternans
and QT dispersion do not appear to be useful for SCD risk
stratification in ER, although evidence is scarce (26). The
ER pattern diminishes and even disappears in response to
exercise both in symptomatic and asymptomatic ER patients, irrespective of ER localization (16,30). Therefore,
treadmill tests do not seem to provide prognostic information. Athletes undergoing pre-participation screening are a
group of particular interest. Early repolarization patterns
(especially in leads V2 to V6) occur in up to 90% of
high-performance athletes (36). Whether this ER preva-

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lence entails an increased arrhythmic risk is unknown,

although mid precordial ER location is generally believed to
be benign. In the absence of reliable data, it seems unreasonable to recommend cessation of sports activities in
asymptomatic athletes with ER (37), even at competitive
levels.
Unexplained syncope associated with an electrocardiographic ER pattern is a particular problem. Both ER and
syncope are very common, affecting 5% and up to 40% of the
general population, respectively. As no clear stratifying criteria
are available, general guidelines for the management of syncope
apply. Familial SCD history, palpitations prior to syncope, and
syncope in the supine position point to increased risk (38). The
sensitivity of electrophysiological studies in patients with ER
and SCD is as low as 34% (16,25). Subcutaneous recording
devices might prove useful (38).

Possible Underlying Mechanisms

Figure 2 provides a schematic representation of potential
mechanisms producing ER. An ECG and action potentials
(APs) recorded from 2 regions of the heart (A and B,
bottom) are shown. Under normal conditions (left), AP
durations are similar and small variations in the timing of
local depolarization and repolarization produce the electrocardiographic QRS complexes and T waves. During the
ST-segment, all cardiac cells are depolarized, so little
current flows. If region A is affected by ER (right), there is
a large voltage gradient between region B, which is still at
plateau potentials, and region A, which is at the resting
potential. Current flow toward the ER region creates
positive ST-segment displacement (ST-segment elevation)
in ECG leads reflecting electrical activity in region A.

Early repolarization

Normal

APs from region B

Depolarization

Repolarization

0 mV
0 mV

0.3 s

-80 mV
-80 mV

APs from region A

QRS
J-wave
0.3 s

T-wave

T-wave

ST-segment

ST-segment

Region B

Region A

ECG

Figure 2

LV
RV

Potential Mechanism of Early Repolarization

Action potentials recorded from regions A (red) and B (blue) are shown (top), together with electrocardiogram (ECG) from region A (middle).
See text for discussion. AP action potential; LV left ventricle; RV right ventricle.

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Regions A and B in Figure 2 could represent different

cardiac regions or just different myocardial layers, associated
with the development of either regional or transmural
voltage gradients, respectively.
To generate the typical ER pattern, it is necessary that
some regions of the myocardium repolarize earlier than others:
generalized ER would cause uniform shortening of the QTinterval, not the ST-segment elevation and J waves that
characterize ER. Variations in a variety of currents can contribute to such repolarization differences (39 43). Figure 3
represents the principal ionic currents involved in the
cardiac AP. Phase 0 AP depolarization is caused by activation of the inward Na-current INa. Transient outward
K-current (Ito) then initiates early (phase 1) repolarization.
Subsequently, inward L-type Ca2-current (ICaL) activation
carries depolarizing charge that supports the AP plateau
(phase 2) against repolarizing K-currents. Finally, activation of delayed-rectifier currents, especially the rapid component IKr, initiates phase 3 repolarization and, in consort
with inward-rectifier currents, repolarizes the membrane

Epi
Endo

INa
ICaL
Ito
IKr
IKs
IKI
INa/Ca
J-wave

1181

back to the resting potential. Increases in repolarizing

current or decreases in depolarizing current accelerate
repolarization. Prominent voltage gradients early in repolarization produce J waves; voltage gradients later in
the AP cause ST-segment elevation. In arterially perfused
canine ventricular-wedge samples, J waves are associated
with phase 1 voltage gradients between endocardium and
epicardium (39), which develop due to the smaller Ito
density present in endocardium compared with epicardium
or mid-myocardium (40). In the same model, ST-segment
elevation can be induced by administration of IKATP openers
or Ca2-channel blockers, the effects of both currents
extending beyond phase 1 to the plateau phase (27).
The mechanisms of ER-induced arrhythmias are incompletely understood. Figure 4 presents one possible scenario
(44). If ER is accelerated with a large Ito, phase 1 notch
increases and/or all-or-none repolarization can occur, producing large voltage gradients. These voltage gradients can
initiate arrhythmogenesis, either by propagation of the AP
dome (phase 2 re-entry) (41) or via boundary currents
analogous to injury currents in acute myocardial infarction
(42) that raise ER cells to threshold and induce spontaneous
activity.
The first gene variants described in patients with ER and
SCD agree with the notion of ionic-current imbalances
favoring accelerated repolarization as causes of the characteristic ECG pattern and arrhythmia susceptibility. The first
mutation identified in a patient with ER-related VF was
found in the KCNJ8 gene encoding the inward-rectifier
ATP-dependent K-channel (35). No functional studies are
available for this variant. Preliminary results indicate a loss-offunction mutation in CACNB2B, an accessory Ca2-channel
subunit, in 1 of 8 genotyped ER patients (43).
Mechanistic considerations may explain clinical aspects of
ER. J waves are enhanced by hypothermia, which can also
cause VF (39). Ionic currents have characteristic temperature sensitivities (45), potentially accounting for hypothermic J waves. Most ionic currents show time-dependent
activation, inactivation, and/or recovery properties and are
strongly influenced by heart-rate changes (46), potentially
accounting for rate-dependent ER manifestations. The
benefit from quinidine is generally attributed to Ito inhibition, which is consistent with the notion that early phase 1
voltage gradients underlie arrhythmogenesis, although
quinidine blocks a variety of ion currents including delayedrectifier K-currents and Na-current as well as Ito.
Relation to Other SCD Syndromes With ER

Figure 3

Schematic Representation of APs in Epicardium

and Endocardium With the Main Underlying Ionic
Currents and Corresponding ECG

AP phases 0 to 4 are indicated. Depolarizing (inward) current are in red, repolarizing

(outward) currents in blue. Endo endocardium; epi epicardium; ICaL Ca2current; IKI inward-rectifier K-current; IKr rapid delayed-rectifier K-current; IK s
slow delayed-rectifier K-current; INa Na-current; INa/Ca Na/Ca2 exchange current; Ito transient outward K-current; other abbreviations as in Figure 1.

Besides acute myocardial ischemia, an acquired condition

that accelerates repolarization and causes SCD (47), BrS
and SQTS also cause early repolarization and IVF. The
basic features of BrS, SQTS, and ER syndrome are summarized in Table 1 (48 50).
Brugada syndrome is defined by a characteristic ECG
pattern including ST-segment elevation in right precordial

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Transmural
voltage
gradient

Epi2

Endo

Epi1

B
Endo

Epi1

Epi2

Figure 4

Potential Mechanism for Early Repolarization Arrhythmogenesis

(A) With enhanced repolarization in regions with prominent Ito, all-or-none repolarization can occur, creating a substrate for arrhythmias. (B) Simultaneous action potentials from 2 epicardial (Epi1 and Epi2) and 1 endocardial site (Endo), and surface ECG. A loss of the action potential dome in Epi1, but not in Epi2, leads to apparent
propagation of the dome from Epi2 to Epi1, inducing re-entry. Adapted, with permission, from Yan et al. (44). Abbreviation as in Figure 2.

leads (7), is often associated with terminal conduction

slowing, and has been closely linked to mutations affecting
Na-channel function, with some cases involving genes
encoding ICaL and Ito (5156). Furthermore, BrS alters cell
repolarization, although whether this is a primary effect or is
secondary to underlying depolarization disorders remains
controversial (57). The right precordial dominance in BrS
may relate to greater right-ventricular Ito density compared
with other cardiac regions (58). The SQTS, with widespread AP-duration decreases reflected by QT-interval
shortening, is caused by gain-of-function K-channel mutations and less commonly loss-of-function Ca2-channel
mutations (8,59 61).
There is considerable overlap between the various syndromes involving accelerated repolarization, and it has been
suggested that they be encompassed by the general term
J-wave syndromes (27). Presumed loss-of-function mutations in Ca2-channels have been described in BrS, SQTS,
and ER syndrome (43,53). Gain-of-function mutations in
IKr and IKs subunits, classically related to SQTS, were
recently also associated with ER (62,63). Early repolarization patterns are common in SQTS patients and reflect

arrhythmic risk (62). Both BrS and ER syndrome have been

described simultaneously in the same individual or in
different members of the same family (14). Among patients
with BrS, an ER pattern in inferolateral leads is found in
11% to 15% of cases (64 66). Whether the presence of ER
increases the arrhythmic risk in patients with BrS remains
controversial. One publication reported a 4-fold increase in
arrhythmia recurrence in patients with BrS and ER (66),
but the findings differ in other series (65).
Unresolved Issues
Perhaps the most striking aspect of the rapidly evolving data
regarding ER is the questions they raise about the pathophysiology and clinical significance of the ER pattern and
about the broader range of arrhythmic conditions involving
accelerated repolarization. We will highlight these by returning to questions raised in the introduction.
What are the basic mechanisms underlying ER and
associated arrhythmias? Although some data are available
from experimental models, many questions about the mechanisms of ER-related arrhythmogenesis remain unan-

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1183

Inherited
Syndromes
ER Involving ER
Table 1 SCD
Inherited
SCDInvolving
Syndromes
Brugada Syndrome

Short-QT Syndrome

Gene mutations/ion current

KCNJ8/IKATP (35)
CACNA1C, CACNB2B/ICaL (43)

ER Syndrome

SCN5A, SCN1B, SCN3B/INa (51,54,55)

GPD1-L/INa (52)
CACNA1C, CACNB2B/ICaL (53)
KCNE3/Ito (55)

KCNH2/IKr (59)
KCNQ1/IKs (60)
KCNJ2/IK1 (61)
CACNA1C, CACNB2B/ICaL (53)

ECG

J-wave; ST-segment elevation

J-wave; ST-segment elevation

Short-QT; peaked T waves

Drug therapy

Quinidine (16)
Isoproterenol (15)

Quinidine (48)
Isoproterenol (49)

Quinidine (50)

ECG electrocardiogram; ER early repolarization; SCD sudden cardiac death.

swered. Recent studies (2527) have placed great emphasis

on the J-wave as an indicator of arrhythmic risk. However,
the pathophysiological role of events corresponding to the
J-wave is unclear. The J-wave occurs immediately after
depolarization, very early in the ST-segment, whereas ERassociated ventricular tachyarrhythmias usually begin much
later, close to the T-wave. Consider the speculation based
on theoretical possibilities illustrated in Figure 5: panel A

shows an endocardial and 2 epicardial APs reproduced from

Figure 4. One epicardial cell (Epi2) shows a typical spikeand-dome pattern with accentuated phase 1 repolarization,
whereas the other (Epi1) has undergone all-or-none repolarization directly from phase 1, showing early phase 3
repolarization. Figure 5B and 5C illustrate the expected
electrocardiographic consequences of Epi1 or Epi2 APs.
Displacements in the ST-segment result from voltage gra-

Transmural
voltage
gradients

Epi2

Endo

Epi2

Epi1

Endo

Epi1

C
B
Endo
Epi2

Endo

J-wave

Epi1
ST-segment
T-wave

J-wave

ST-segment

Figure 5

T-wave

ST-segment
T-wave

ER Effects on Action Potentials and ECG, Illustrating the Potential Role of J-Wave as a Marker of ER Risk

(A) Early repolarization (ER) can enhance phase 1 notch (Epi2) or cause all-or-none repolarization from phase 1 (Epi1). (B) Enhanced phase 1 notch causes prominent
J-wave. (C) All-or-none repolarization does not cause J-wave but produces large transmural repolarization gradients that persist when Epi1 APs have regained excitability,
potentially causing ectopic activity (dashed lines). (D) Variable AP repolarization responses to ER generates both prominent J waves and ectopic activity. Abbreviations
as in Figures 2 and 3.

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dients illustrated by the violet arrows. Epi2 APs have a large

voltage gradient early in repolarization and generate large J
waves (Fig. 5B); the voltage gradient then rapidly decreases,
resulting in little ST-segment elevation. In contrast, Epi1
APs produce an increasing voltage gradient during the
ST-segment (Fig. 5C). Because the voltage gradient continually increases between phases 1 and 3 of Epi1, there
would be no discrete J-wave but considerable ST-segment
elevation, and the large depolarizing voltage gradient following Epi1-repolarization could reactivate Epi1 cells leading to early coupled ectopy (dashed lines). A combined
scenario with heterogeneous accelerated repolarization is
illustrated in Figure 5D, with some cells showing deep
notches and others all-or-none repolarization from phase 1,
producing prominent J waves along with ST-segment elevation and arrhythmogenesis. The enhancement of the AP
dome that can occur with Epi2 APs increases the risk by
creating large intraepicardial voltage gradients. In addition,
steep repolarization gradients could produce unidirectional
block and re-entry in response to focal ectopic activity. In
this schema, J waves might be markers of ER arrhythmia
risk, rather than directly reflecting the arrhythmogenic
mechanism. Figure 4 shows another notion of arrhythmogenesis in ER more directly implicating the J-wave, with
propagation of the AP dome causing phase 2 re-entry.
Another important issue is the unknown basis of regional
ER. Why is ER located primarily in inferior leads in some
individuals and lateral leads in others? Localization must
reflect regional control of repolarization, which is presently
poorly understood. In most studies of ER, only patients
with inferior or lateral ER are considered (16,18), presumably to avoid contamination with BrS patients. However,
this begs the question of whether some (perhaps many) BrS
patients simply have a right precordial variant of ER.
Striking similarities between ER and BrS include male
predominance, peak of SCD incidence at the fourth decade
of life, slow heart-rate dependence, and favorable responses
to quinidine and isoproterenol. However, the clear accentuation typically produced by Na-channel blockers in BrS
is not seen in ER (12,14,15,17,32), highlighting probable
differences in underlying ionic mechanisms. It is also intriguing that the J-wave was initially considered a depolarization event: is it possible that the right precordial terminal
conduction slowing typical of BrS patients is in some cases
simply a J-wave? Despite extensive investigation, only about
20% of BrS patients have detectable mutations, most affecting Na-channel function. Could many genotype-negative
BrS patients simply be right precordial ER variants?
How can ER-related SCD be predicted and prevented? At
the moment, we have data about the characteristics of
malignant ER patients presenting with SCD, and some
knowledge about apparently healthy individuals with ER.
However, we have very little information connecting the
two. A crucially important issue is whether there are two
discrete populations, one with benign ER (a true normal
variant with no risk of adverse outcomes) and another with

JACC Vol. 56, No. 15, 2010

October 5, 2010:117786

malignant ER at risk of SCD, or whether all individuals

showing ER are at risk of SCD under appropriate circumstances. Further longitudinal and observational studies comparing malignant ER patients with asymptomatic ER controls are needed to clarify their relative characteristics.
Studies of genetic variability could be particularly valuable in
defining gene variants that distinguish benign from malignant ER, providing insights into risk prediction, racial, and
sex features, and pathophysiological mechanisms. Geneexpression profiling may provide new insights into the
mechanisms underlying ER syndromes, including the role
of regional and gender-related factors, and may eventually
be of diagnostic and prognostic value (69 71). Athletic
activity and high-level training strongly predispose to ER,
yet the incidence of IVF in trained athletes is fairly low.
Does this support the notion that individuals with benign
ER are not at risk? Are there individuals at risk of malignant
ER for whom exercise training must be prohibited?
The prevention of ER-related SCD is closely related to
accurate risk stratification. In addition, it presumes effective
preventive measures. At present, the only definite way to
prevent SCD is with ICDs. These can only be justified in
individuals at very high risk, such as survivors of ER-related
SCD. The identification of other high-risk ER subgroups
meriting ICD implantation would be helpful. However, less
aggressive approaches for individuals at lower risk would
also be desirable. Quinidines efficacy has been attributed to
Ito inhibition, but the basis of its efficacy is unclear because
quinidine also affects other currents. It is presently feasible
to develop highly selective Ito blocking compounds (67,68),
which might prevent SCD in a range of ER-associated
conditions (e.g., acute myocardial infarction, BrS, SQTS,
and malignant ER) and provide an important test of
presumed pathophysiology. Further insights into the role of
heart rate and autonomic tone are needed. Bradycardia as an
exaggerator of ER could explain ER enhancement in
athletes and nocturnal occurrence of ER-associated SCD;
tachycardia could account for the ER-reducing effects of
exercise and enhanced adrenergic tone. If so, pacemaking to
prevent bradycardia or increase resting heart rate might be
indicated in some at-risk individuals. The direct role of
ionic-current modulating effects of autonomic tone (15,22)
requires investigation. Heart rate-independent autonomic
effects would have specific therapeutic implications.
How should the physician advise a patient with this ECG
variant that was until recently considered normal? Present knowledge is inadequate for detailed counseling of
asymptomatic individuals with ER patterns. The overall risk
is low, but epidemiological studies (18) suggest that it is not
0, and SCD is such a devastating event that even a small risk
is disturbing. This issue has complex human, medical, and
potential legal implications and further research, of the type
discussed, is essential to clarify the outcome predictors in
asymptomatic ER subjects. For now, asymptomatic young
and physically active individuals, particularly those with ER
restricted to precordial leads, can be reassured that the

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Benito et al.
Early Repolarization and Sudden Death

JACC Vol. 56, No. 15, 2010

October 5, 2010:117786

available evidence indicates no increased risk. However, we

need to be able to more accurately estimate risk in all ER
subjects, offer preventive therapy when risk is elevated, and
understand underlying mechanisms to move forward in risk
stratification and management. Clearly, there is a lot of
work to do.
Reprint requests and correspondence: Dr. Stanley Nattel, Montreal Heart Institute, 5000 Belanger Street, Montreal, Quebec
H1T 1C8, Canada. E-mail: stanley.nattel@icm-mhi.org.

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Key Words: early repolarization y idiopathic ventricular fibrillation y

sudden cardiac death.

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Clinical and Mechanistic Issues in Early Repolarization: Of Normal Variants

and Lethal Arrhythmia Syndromes
Begoa Benito, Eduard Guasch, Lena Rivard, and Stanley Nattel
J. Am. Coll. Cardiol. 2010;56;1177-1186
doi:10.1016/j.jacc.2010.05.037
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