Clinical interest in electrocardiographic (ECG) phenomena of early ventricular repolarization
(EVR) has been rekindled recently mainly because of their clinically established association
with fatal cardiac arrhythmias, particularly in otherwise healthy individuals with
no (or minimal) structural diseases of the heart. ECG phenomena of EVR have often
been misdiagnosed, misinterpreted, or undermined. This happened mainly because of
prevailing opinion of the"benign" or "misleading" nature of various EVR phenomena.
For instance, early repolarization changes consistent with Brugada syndrome have been
interpreted "innocent" and overlooked for decades until 1992 . Another example
- so-called "early repolarization syndrome" (ERS) that universally and unequivocally
has been regarded as "normal", "normal variant", "benign early repolarization" until
2000 . In 2008, seminal article by Haïssaguerre et al . accompanied by editorial
comments by Wellens  and letter to the editor by Nam et al . brought clinical
attention to an increased prevalence of the ERS among patients with a history of idiopathic
ventricular fibrillation (VF).
The ECG phenomena of EVR include (but not are limited to):
"Slurring or notching" of the QRS complex (with or without J-deflections)
J-waves (with or without ST-segment elevation).
The clinical validity of ECG manifestations of EVR as makers of sudden cardiac death
(SCD) and their utility in risk stratification are not well defined. In addition,
it is common for such ECG phenomena to vary significantly depending upon a variety
of intrinsic cardiac and extracardiac factors. The main focus of this review is to
characterize the ECG patterns of the EVR with a special focus on the ERS and its arrhythmogenic
Ventricular repolarization begins when ventricular depolarization ends. In the normal
heart, the evolution of depolarization into repolarization is relatively short process,
and the magnitude of the overlap between the latest depolarization and the earliest
repolarization does not exceed 10 msec . The duration of this temporal overlap
between the end of depolarization and the beginning of repolarization is greatly influenced
by various physiological and pathological, cardiac and extracardiac conditions that
affect either: (a) propagation of the excitation wave through ventricular wall or
(b) recovery of its excitability, or (c) both. Among intrinsic cardiac factors are:
An intrinsic configuration of the early phase of the actions potentials in different
ventricular layers (endomyocardium, midmyocardium, and epicardium)
A modification of the time-course of repolarization across the ventricular wall (transventricular
In a normal ECG, the transition of ventricular depolarization into ventricular repolarization
corresponds on the surface ECG to the
. The J-point defined as the point at which there is abrupt transition from the QRS
complex to the ST-segment. Deviation of the J-point from the isoelectric line leads
to the presence of a
, which is a common ECG feature of ERS, but also seen in acute myocardial ischemia,
hypercalemia, and various intraventricular conduction disturbances. A J-deflection
inscribed on either the downsloping limb of the QRS complex or S wave is commonly
regarded as a
, whereas a smooth and prolonged transition from the QRS segment to the ST segment
. Increased amplitude and duration of the J-deflection that takes the shape of a 'dome
or a hump" is usually described as a
Noteworthy to emphasize that a clear distinction between the delayed conduction and
the EVR cannot always be made on the basis of an ECG alone. Nevertheless, distinguishing
the two is very important since commonly EVR presents greater arrhythmia risk than
a delayed intraventricular conduction, especially in otherwise healthy individuals.
To limited extent, depolarization and repolarization processes can be differentiated
based by their differences with respect to the heart rate, different cardiac drugs,
and neurotransmitters (see below). The signal-averaged ECG could be helpful diagnostic
tool but of limited clinical value in many cases , and the search for new ECG
tools and markers to differentiate these two processes is accelerating.
"Slurring or Notching" of the QRS Complex
In 1998, Garg and his associates  reported a case of "familial sudden cardiac death
associated with a terminal QRS-abnormality on surface 12-lead electrocardiogram".
The abnormal low-amplitude deflections in the downsloping limp of the QRS complex
in leads II, III, aVF and I, aVL and V6 were coincident with the late potential on
the signal-averaged ECG. This deflection appeared to be more prominent after procainamide
or beta-blockers and normalized after quinidine. Moreover, sustained polymorphic ventricular
tachycardia, which degenerated to VF was easily inducible during programmed stimulation
from the right ventricular apex, despite administration of procainamide or atenolol.
The clinical significance of these ECG findings is not fully understood at present
and further investigation is warranted.
Different names have been used at different time for the J-wave. They include "camel
hump sign","hathook junction", "K wave", "H wave", "late delta wave", "current of
injury", "J point wave", "hypothermic wave", "hypothermic hump", "Osborn wave". J-waves
can be classified as:
Clinical as well as experimental data linking hypothermic J-waves and cardiac arrhythmias
remain sparse and somewhat contradictory; the occurrence of ventricular tachyarrhythmias
associated with hypothermic J-wave varies from 0 to almost 100% . Sodium channel
blockers, such as procainamide and lidocaine, are ineffective, indeed proarrhythmic
in both the prevention and treatment of the malignant ventricular tachyarrhythmias
in hypothermic patients during their rewarming .
ECG changes resembling those in hypothermia-induced J-waves have been observed in
a various clinical and experimental settings with normal body temperature, such as
acute myocardial ischemia, acute pulmonary thromboembolism, right ventricular infarction,
electrolyte or metabolic disorders, pulmonary or inflammatory diseases, or abnormalities
of central or peripheral nervous system, intoxication by heterocyclic antidepressant
or cocaine, and many other abnormal conditions . Among those clinical situations,
prominent J-waves most frequently are observed in acute myocardial ischemia and hypercalemia,
and their arrhythmogenic potentials in most clinical settings are chiefly dependent
upon the underlying disease.
In the absence of any structural cardiac abnormalities or extracardiac diseases, changes
of EVR can be classified as primary or "idiopathic". Several forms of idiopathic appearance
of a J-wave in human with or without accompanying ST-segment elevation have been described.
Among them, the most investigated is so-called ECG marker of Brugada syndrome. Idiopathic
J-wave followed by downsloping ST-segment elevation with inverted T-waves in the right
chest leads is an ECG hallmark of the "typical" Brugada syndrome.
However, in many clinical cases of symptomatic Brugada syndrome (atrial and/or ventricular
tachyarrhythmias or SCD), the pattern of ST-T abnormalities and/or their ECG "localization"
is different from that in the "typical" Brugada Syndrome. In such cases, the terms
"atypical" or "J-wave - like' are appropriate. Clinically noteworthy that J-wave-like
ECG abnormalities in leads other that the right precordial (e.g. inferior or lateral)
("atypical" Brugada syndrome) have been also described in otherwise healthy individuals
prone to paroxysmal ventricular tachycardia/fibrillation.
Early Repolarization Syndrome
The term "early repolarization syndrome" was introduced nearly half a century ago
and has traditionally been regarded as idiopathic and benign or "innocent"  or
"misleading"  ECG pattern of EVR until 2000 . The ERS has been ascribed a number
of names, including "early repolarization", "early ventricular repolarization', 'benign
early repolarization", "benign J wave", "nonspecific changes of ventricular repolarization",
"repolarization variant", "normal variant RS-T segment elevation", and "juvenile or
unconventional ST-T pattern" and cetera to describe the "characteristic" ECG pattern
of J-deflection followed by horizontal ST-segment elevation in the mid-precordial
To avoid further confusion and inconsistencies with terminology, we prefer to use
the term "early repolarization syndrome", acknowledging at the same that this term
is not the best one to use in the cases of asymptomatic forms of EVR. By its own definition,
any clinical syndrome is a combination of signs and symptoms that occur together and
characterize a particular abnormality. The term "syndrome" is best reserved for a
description of clinical manifestation of the disease. In this context, the "true ERS"
is best defined as an arrhythmogenic entity that is characterized by (a) ECG marker
of ERS that is associated with (b) arrhythmogenic complications, including SCD, and/or
family history of SCD in otherwise healthy individual.
The prevalence of ERS varies between 1%  and 2% . It is more commonly seen
in young individuals (27.5%) , especially those predisposed to vagotonia, and
shows a clear male preponderance (77%) . The syndrome is also often observed in:
Cocaine users 
Obstructive hypertrophic cardiomyopathy 
Defects and/or hypertrophy of the interventricular septum .
The electrocardiographic manifestation of ERS is often dependent on heart rate, normalizing
during exercise or with rapid pacing, as well as with advancing age . Familial
occurrence of the syndrome has been observed [20,21]. Although early studies were
interpreted to suggest that the syndrome is more prevalent in the Black population,
more-recent studies challenge this notion .
In 2000, based on preclinical experimental work from Dr. Charles Antzelevitch, it
has been suggested that: (a) ERS should not be considered as normal or benign ECG
abnormality a priori, unless otherwise proven, as generally thought and (b) under
certain conditions known to predispose to ST-segment elevation, patients with ERS
may be at greater arrhythmogenic risk .
The classical ECG pattern of ERS consists of: (a) prominent notch or slur on the downsloping
portion of the QRS complex, or J-deflection, (b) followed by diffuse upward ST segment
concavity concordant with the QRS complex, and (c) positive T wave in the same lead.
Additional ECG feature include:
Localization of the ECG pattern of ERS in scalar ECG. Mid-to-lateral precordial leads
V2-V4(5) have been recognized as showing the most prominent repolarization changes
consistent with ERS. Noteworthy, similar changes might appear in other leads but to
a lesser extent
Reciprocal ST segment depression in aVR
"Waxing and waning" of the ST-T segment over time
Often, ERS is associated with shorter-than-normal QT interval duration, even adjusted
to the heart rate.
Nevertheless, in many clinical instances, it is still very difficult to distinguish
subjects with ERS from those with the Brugada syndrome or various intraventricular
conduction blocks, or Short QT syndrome based solely on a resting ECG. Furthermore,
the ECG alterations in response to changes in heart rate, drugs effects, and autonomic
tone observed in ERS are very similar to those observed (a) under hypothermic conditions
and (b) the Brugada syndrome (Table 1).
Many clinical features of ERS are similar to that of Brugada syndrome, including (a)
predominance in young otherwise healthy males, (b) predisposition to familial occurrence,
(c) in many individuals, a transient normalization of ECG manifestation, and (d) ERS
similar responses to drugs and autonomic modulation.
Two major features permit differentiation of the ECG signatures of ERS and the Brugada
syndrome: (a) pattern and (b) leads specificity. The elevated ST-segment in ERS is
usually localized in leads V2-V4(5) and has an upward concavity with positive T-wave
polarity accompanied by a notched (or slurred) J-deflection. In contrast, the ECG
of Brugada patients generally displays a prominent J-point elevation (J-wave), followed
by a downsloping ST segments and negative T-wave in the right precordial leads V1-V3
("typical") or other leads ("atypical").
It is often difficult to distinguish subjects with ERS from those with the Brugada
syndrome, especially when the latter also display intraventricular conduction slowing
or block. In 1993, Aizawa and his colleagues  described several patients with
idiopathic ventricular fibrillation in whom they found "bradycardia-dependent intraventricular
block". The common ECG features of these patients included: (a) incomplete right bundle
branch block, (b) prominent "notch" on downsloping limb of the QRS complex in leads
V3-V5, II, III, and aVF, (c) elevated ST segment with positive T waves leads V2-V3,
and (d) rate (deceleration) - dependent accentuation of the prominence of the "notch".
The dynamicity of ECG changes in ERS and Brugada syndrome is also confounding. When
the clinical history is malignant, an invasive electrophysiological study examining
the inducibility of ventricular tachycardia/fibrillation may be useful in assessing
Interestingly, ECG changes consistent with the Brugada syndrome have also been referred
to as a benign repolarization variant or "Ideiken phenomenon" for more than three
decades and some patients having such ECG abnormalities have been described as "unwitting
victims of electrocardiography" .
No doubt, the intrinsic capability of the standard 12-lead ECG are significantly limited
in the differential diagnosis of the ERS, since only a small portion of the available
diagnostic information can be obtained from conventional scalar 12-lead ECG tracings.
The search for new additional and more advanced and sophisticated computer-assisted
methodologies and ECG markers that can help to differentiate ST-segment elevations
in ERS from other ECG phenomena of EVR (e.g. Brugada syndrome, acute ischemia) have
intensified in most recent years. The "three-dimensional (3D) approach" is expected
to be valuable in EVR evaluation. Some of those 3D - ECG markers (e.g. ST-T and QRS-T
angles) are already in their "clinical validation" stages of development (1).
Possible Cellular and Ionic Mechanisms
Concordant with the QRS complex, ST segment elevation is most commonly recognized
as a sign of acute myocardial damage, often associated with the development of cardiac
arrhythmias. The electrophysiological nature of the ST-segment elevation in ERS, whether
idiopathic or due to so-called "current of injury", has been investigated by means
of a direct-current magnetocardiogram, which, in contrast to conventional 12-lead
ECG, is capable of determining a TQ interval shifts. The results showed clearly that
ST-segment shifts in subjects with ERS are unrelated to ischemic injury .
One might also explain the principal difference between ERS and Brugada syndrome based
on an abbreviation of the action potential due to loss of its "dome" resulting in
the development of a very significant transmural as well as epicardial dispersion
of repolarization and refractoriness, setting the stage for both phase 2 and circus
movement reentry culminating in much more severe arrhythmogenic manifestations of
the Brugada syndrome if compared with ERS .
Some believe that parietal (myocardial) conduction defects (delayed conduction) could
contribute to both the ECG manifestation and the arrhythmogenic potentials of the
different ECG phenomena of EVR.
Modulation by Drugs, Rate, and Neurotransmitters
The changes in the magnitude of the EVR abnormalities in ERS and Brugada syndrome,
like a hypothermic J wave, display qualitatively similar responses to a variety of
drugs as well as to changes in rate and autonomic tone (Table 1) :
Slowing of heart rate exaggerates J-waves and ST-segment elevation, while increase
in heart rate during exercise or following isoproterenol reduces or even eliminates
these ECG abnormalities
Sodium channel blockers (known to unmask the Brugada syndrome) increase ST-segment
elevation in ERS subjects and hypothermic J-waves
Sympathetic stimulation and β-adrenergic agonists normalize the ST-segment in both
syndromes, whereas β-adrenergic blockers augment ST-segment elevation in both, while
propranolol increases its magnitude and its toxicity may even induce classical pattern
The Role of Nervous System
Clinical and experimental studies point to high spinal cord injury as a cause of ERS-like
changes in the ECG. High cervical spinal chord injury can lead to significant deterioration
or even complete disruption of the cardiac sympathetic activity, leaving parasympathetic
activity unopposed . Parasympathetic activation has an opposite effect in both
syndromes, causing ST segment elevation due to depression or loss of the action potential
plateau (see below). ECG patterns "wax and wane" in both syndromes, possibly due to
variations of autonomic activity .
In vast majority of cases, ERS is not a malignant EVR syndrome per se, unless otherwise
proven. However, the similarities between the Brugada syndrome and ERS in response
to rate, neuromodulation and pharmacologic agents strongly suggest a parallelism of
While ERS has long been considered to be benign, in experimental models, the ECG signature
of ERS can be
to that of the Brugada syndrome [2,26,27]. This raises the possibility that ERS may
not be as benign (unless otherwise proven) as generally believed, and that under certain
conditions known to predispose to ST-segment elevation, ERS subjects may be at increased
risk. In considering these possibilities, it is instructive to remember that (a)
the Brugada syndrome was regarded as benign for more than three decades, and (b) that
one syndrome can be readily converted to the other in experimental models involving
the wedge preparation.
One hypothesis presumes that depression of the epicardial, but not endocardial, action
potential plateau creates a transmural gradient that manifests on the scalar ECG as
a complex ST-segment elevation with a positive T-wave. As such the cellular substrate
is not arrhythmogenic, but in case of further increase in net repolarizing current
as a result of complete loss of the epicardial action potential dome and the attendant
development of a large transmural dispersion of repolarization could become arrhythmogenic.
This proposed mechanism also explain the highly arrhythmogenic character of the Brugada
syndrome and apparently benign exceptions.
Alternative hypothesis is based on assumption that the delayed (parietal) intraventricular
conduction delay in the proximity of interventricular septum (mid-precordial leads
could contribute to the ECG phenomenon of ERS and its potential link to electrical
It is important to emphasize that these hypotheses remain to be more rigorously tested
and that the distinct nosologic entity that is referred as the ERS needs to be more
fully delineated within the framework of what we have learned about the Brugada syndrome
in recent years. A careful clinical history and invasive electrophysiological studies
may be required to determine whether or not the early ventricular repolarization abnormalities
in a given patient are benign or malignant.
Summary, Clinical Implementation, and Future Directions
The available clinical data suggest that the different ECG phenomena of the EVR syndromes
often share similar ECG presentations, mechanisms with wide range of their arrhythmogenic
potentials. ECG similarities between different ECG phenomena of EVR raise certain
concerns for their misdiagnosis and clinical relevance.
In our opinion:
ERS, as a diagnosis, should not be regarded as either benign or malignant a priori
unless otherwise proven.
Clinical judgment based on clinical presentation ("arrhythmogenic" anamnesis), family
history or syncope/SCD, potential use of cardio-active drugs, including psychotropic
medications is the most essential in the risk stratification of the ERS subject. Special
attention should be devoted to the family history of primary EVR abnormalities and/or
Additional diagnostic work-up, such as tilt-test, signal-averaging ECG, and electrophysiological
studies with or without drug testing, should be considered on the case-by-case basis
upon physician's discretion. Genetic screening of ERS subjects at risk, once available,
will be one of the most important diagnostic tools to identify and/or confirm the
diagnosis of primary electrical abnormalities/diseases of the EVR.
It is important to keep in mind that ERS subjects might be predisposed to the drug-induced
Standard 12-lead ECG is very valuable diagnostic tool to identify ERS subjects, yet
its clinical utility in the risk stratification is of limited intrinsic value. New
ECG technologies, methodologies, and markers should be developed and clinically validated
to help to identify and differentiate ERS from other forms of EVR as well as to stratify