Chapter 2

Brugada Phenocopy: Definition,

Diagnosis, and Differentiation
From True Brugada Syndrome
Byron H. Gottschalk
London Health Sciences Centre, Western University, London, ON, Canada

INTRODUCTION TO BRUGADA PHENOCOPY

With the recognition that patients may present with a Brugada ECG pattern in
the context conditions not attributable to Brugada syndrome (BrS), there was a
need to further characterize these “phenocopies” to facilitate clinical decision-
making and research. Brugada phenocopies (BrPs) are clinical entities that
present with an ECG pattern identical to either the type-1 or type-2 Brugada
patterns, yet differ etiologically from true congenital BrS [1–4]. The pattern
presents in association with an identifiable condition and, upon resolution of
that condition, the ECG pattern normalizes. BrP may not be due to the same
sodium channel abnormality as BrS, or may be only transient while the underly-
ing condition persists [5–7]. Indeed, the defining feature of BrP is the absence
of true congenital BrS.

CLASSIFYING BRP
BrPs are classified according to the presenting ECG morphology: type-1 BrP,
when the patient presents with a type 1 Brugada ECG pattern; or type-2
BrP, when the patient presents with a type-2 Brugada ECG pattern. Cases of BrP
are further subclassified as A, B, and C (Table 2.1). Class A includes cases of
definitive BrP, in which all mandatory diagnostic criteria have been met, includ-
ing negative provocative challenge with a sodium channel blocking agent. Class
B includes cases highly suspected to be BrP; however, the mandatory diagnostic
criteria are incomplete. These are cases where a provocative challenge is not
possible due to factors such as the patient being deceased, lost to follow-up, or
unwilling to undergo further testing. Class C includes highly suspected cases of
BrP; however, provocative testing was not justified such as in cases with recent
surgical right ventricular outflow tract manipulation or due to ECG filter modi-
fication [8]. In essence, a Class C may not require testing with sodium channel
Brugada Phenocopy. http://dx.doi.org/10.1016/B978-0-12-811151-2.00002-X
Copyright © 2018 Elsevier Inc. All rights reserved. 11
12 Brugada Phenocopy

TABLE 2.1 Morphological Classification System of Brugada Phenocopy

Type
  Type-1 BrP: Brugada phenocopy with a typical type-1 “coved” Brugada ECG
morphology
  Type-2 BrP: Brugada phenocopy with a typical type-2 “saddleback” Brugada ECG
morphology
Class
  Class A: All mandatory BrP diagnostic criteria are complete, including provocative
challenge with a sodium channel blocking agent such as ajmaline, flecainide, or
procainamide
  Class B: Highly suspected BrP; however, not all mandatory criteria are complete
  Class C: Highly suspected BrP; however, mandatory provocative challenge with a
sodium channel blocker not justified
BrP, Brugada phenocopy; ECG, electrocardiogram.
Source: Adapted from Gottschalk B, Anselm DD, Baranchuk A. Brugada phenocopy: morphological
classification and importance of provocative testing. Ann Noninvasive Electrocardiol 2014;19:604–5.

blockers, as underlying cause of the ECG Brugada pattern is easily identifiable

and reproducible.

DIAGNOSIS OF BRP AND ITS DIFFERENTIATION FROM BRS

Establishing a clear diagnostic distinction between BrP and BrS is of the ut-
most importance. The fact that BrS may occur spontaneously, with no personal
or family history of suggestive of the condition and in the absence of defined
genetic abnormalities, makes differentiating between the two conditions chal-
lenging [5,7]. Current recommendations for diagnosis and risk stratification
of BrS rely on a combination of clinical factors, presenting ECG morpholo-
gies, and positive provocative testing with a sodium channel blocking agent.
Differentiating between BrP and BrS is important because patients with BrS are
at risk of sudden cardiac death (SCD), may require an implantable cardioverter-
defibrillator, and should refrain from drugs with sodium channel blocking prop-
erties [2,5,9]. In a similar fashion, BrP is a clinical diagnosis that requires the
clinician to take into account multiple clinical and electrocardiographic factors
[1]. The clinical implications of BrP, however, remain unknown. Therefore, cur-
rent treatment recommendations for BrP focus on resolution of the underlying
condition as further intervention has not been investigated or validated [2]. In
an effort to facilitate this distinction, a systematic diagnostic approach for BrP
was developed and discussed in the following sections.

Identification of a Brugada ECG Pattern

Familiarity with Brugada ECG patterns is essential to the recognition of BrP
or BrS as being part of the differential diagnosis to a patient’s presentation.
 Definition, Diagnosis, and Differentiation Chapter | 2 13

FIGURE 2.1  Comparison of various type-1 Brugada phenocopies. (A) True congenital type-1
Brugada syndrome electrocardiogram shown in comparison to (B) congenital hypokalemic periodic
paralysis (type-1B BrP), (C) acute inferior ST-elevation myocardial infarction with right ventricular
involvement (type-1A BrP), (D) concurrent hyperkalemia, hyponatremia, and acidosis (type-1A
BrP), and (E) acute pulmonary embolism (type-1B BrP). Numbers under figures are International
Registry of Brugada Phenocopies identification numbers. BrP, Brugada phenocopy. (Reproduced
with permission from Anselm DD, Gottschalk BH, Baranchuk A. Brugada phenocopies: consid-
eration of morphologic criteria and early findings from an international registry. Can J Cardiol
2014;30:1511–5).

The type-1 (coved) Brugada ECG pattern is defined by a high takeoff ST-
segment elevation, ≥2 mm, followed by a downsloping concave or rectilinear ST
segment and a negative symmetric T-wave (Fig. 2.1). The type-2 (saddleback)
Brugada ECG pattern presents with a high takeoff r′ ≥ 2 mm from the isoelec-
tric baseline, followed by a convex ST-segment elevation of ≥0.05 mV with a
variable T-wave in lead V1 and a positive or flat T-wave in lead V2 (Fig. 2.2)
(see Chapters 4 and 5) [7]. The ECG patterns found in BrP and BrS are identical
and cannot be used to distinguish between the two conditions [3,4].

Recognition of an Identifiable Underlying Condition

that may Cause the Observed ECG Changes
Most patients with BrP present with an underlying complaint that is further
investigated and the pattern is incidentally found. BrP may be found in a multi-
tude of clinical circumstances that have been characterized in six distinct etio-
logical categories: (1) metabolic conditions, (2) mechanical compression, (3)
ischemia, (4) myocardial and pericardial disease, (5) ECG modulation, and (6)
miscellaneous (Table 2.2) [1,10]. Within each group, there may be several un-
derlying causes. For example, the category of metabolic conditions includes
cases of hypokalemia, hyperkalemia, hypophosphatemia, hyponatremia, and
acute toxicities [11–20]. The miscellaneous category includes cases such as
14 Brugada Phenocopy

FIGURE 2.2  Comparison of various type-2 Brugada phenocopies. (A) True congenital type-2
Brugada syndrome shown in comparison to (B) congenital pectus excavatum causing mechanical
mediastinal compression (type-2A BrP), (C) acute pericarditis (type-2A BrP), (D) after accidental
electrocution injury (type-2A BrP), and (E) as a result of using inappropriate high-pass electro-
cardiographic filters (type-2C BrP). Numbers under figures are International Registry of Brugada
Phenocopies identification numbers. BrP, Brugada phenocopy. (Reproduced with permission from
Anselm DD, Gottschalk BH, Baranchuk A. Brugada phenocopies: consideration of morphologic
criteria and early findings from an international registry. Can J Cardiol 2014;30:1511–5).

TABLE 2.2 Etiological Categories of Brugada Phenocopy

Etiological categories
1. Metabolic conditions
2. Mechanical compression
3. Ischemia and pulmonary embolism
4. Myocardial and pericardial disease
5. ECG modulation
6. Miscellaneous
ECG, Electrocardiogram; RVOT, right ventricular outflow tract; SCN5A, sodium channel voltage-
gated type-V alpha subunit.
Source: Adapted from Anselm DD, Baranchuk A. Brugada phenocopy: redefinition and updated
classification. Am J Cardiol 2013;111:453.

BrP in the context of electrocution, neurological injuries, and surgical repair

of congenital heart disease [21–24]. There are many underlying conditions that
may present with a Brugada ECG pattern, with new etiologies being presented
in the literature frequently. It is important for the clinician to consider this in his
or her approach to the patient with a Brugada ECG pattern.

Resolution of the ECG Pattern

A defining characteristic of BrP is the resolution of the ECG pattern once
the underlying condition has been treated. If BrP is a phenomenon caused by
an underlying medical condition, common sense dictates that treatment of this
 Definition, Diagnosis, and Differentiation Chapter | 2 15

condition will result in resolution of the ECG pattern. Indeed, this is what we
have seen thus far in clinical cases of BrP. Consequently, it is imperative that
the clinician performs serial ECGs throughout the treatment of a patient who
has presented with a Brugada ECG pattern. However, it is important to note
that the changes seen on ECG may be dynamic and are often concealed. Even
in patients with true BrS, these changes may only be seen when “unmasked” by
certain drugs or febrile states [5,25]. This adds another element of complexity
to the distinction between the two conditions and highlights the importance of
taking multiple factors into account. The disappearance of a Brugada ECG pat-
tern does not, with certainty, suggest a case of BrP rather than BrS and the only
factor that favors BrP is the immediate resolution of the ECG upon resolution
of the underlying condition.

Low Pretest Probability for BrS

BrS is an inherited channelopathy that may result in syncope or SCD. In taking
a history, it is essential to include questions about a history of syncope, palpita-
tions, or aborted SCD. In addition, a family history suggestive of sudden and
unexpected deaths (such as fatal car accidents or death during sleep), syncope,
or a diagnosis of BrS raises the clinician’s suspicion for BrS rather than BrP.
Asking about family members admitted with life-threatening arrhythmias or
having been implanted with implantable cardioverter-defibrillators may also be
of use. In contrast, to date, there is no evidence that BrP displays characteristics
of familial inheritance. In our experience with patients in whom BrP has been
diagnosed, there is no family history of a Brugada ECG pattern.

Negative Provocative Testing

Provocative testing with a sodium channel blocking agent is of the utmost im-
portance in patients where there is suspicion for BrS. As previously mentioned,
a positive provocative test suggests BrS and therefore should result in the pa-
tient undergoing risk stratification. A negative provocative test in a patient who
meets the diagnostic criteria for BrP confirms the diagnosis and suggests a dif-
ferent pathophysiological mechanism behind the ECG pattern. This test should
only be performed in a center that is fully equipped for resuscitation with the
patient closely monitored and should be performed after resolution of the condi-
tion that caused the ECG presentation (once the ECG has normalized). The test
is not mandatory if there was surgical manipulation of the right ventricular out-
flow tract within 96 h of the presenting Brugada ECG pattern. An IV infusion of
any one of the following drugs can be used for the provocative challenge [26]:
l Ajmaline at 1 mg/kg over 5 min
l Flecainide at 2 mg/kg over 10 min
l Procainamide at 10 mg/kg over 10 min
l Pilsicainide at 1 mg/kg over 10 min
16 Brugada Phenocopy

FIGURE 2.3  Electrocardiograms from a Brugada syndrome patient prior to provocative

testing with ajmaline (control) and after provocative testing at 2 and 5 min. Note the produc-
tion of a type-1 Brugada ECG pattern indicating a positive test. (Figure provided by Dr. Raimundo
Barbosa-Barros).

Use a continuous ECG recording at a speed of 10 mm/s to monitor. The test

is considered positive if a type-1 Brugada ECG pattern is reproduced (Fig. 2.3).

Negative Genetics Testing for SCN5A Mutations

While helpful when positive, this test is not mandatory given its low sensitiv-
ity for BrS. The SCN5A mutation is identified in only 20%–30% of probands
affected by true BrS [6]. As a consequence, a negative result does not confirm
BrP and eliminate the possibility of BrS, but a positive result will eliminate
the diagnosis of BrP. Table 2.3 summarizes the diagnostic criteria for BrP and
serves as an approach to differentiating between BrP and BrS. The possibilities
of genetic testing in BrP are discussed in Chapter 16.

THE FUTURE OF BRUGADA PHENOCOPY

The next important steps in BrP research will involve the development of exper-
imental models designed to fully understand the mechanisms behind BrP (see
Chapter 16). Through experimentation, we hope to develop an understanding as
to whether BrPs are the result of transient sodium channel dysfunction that is
not reproduced by sodium channel blocking agents, or whether the key to the
 Definition, Diagnosis, and Differentiation Chapter | 2 17

TABLE 2.3 Brugada Phenocopy Diagnostic Criteria

1. Presenting ECG pattern is of a type-1 or type-2 Brugada morphology
2. The patient presents with an identifiable underlying condition
3. The ECG pattern normalizes after resolution of the underlying condition
4. There is a low clinical pretest probability of true Brugada syndrome determined by
lack of symptoms, medical history, and family history
5. Negative provocative testing with sodium channel blocking agents such as ajmaline,
flecainide, or procainamide
6. Provocative testing is not mandatory if surgical RVOT manipulation has occurred
within the last 96 h
7. The results of genetic testing are negative (desirable but not mandatory because
the SCN5A mutation is identified in only 20%–30% of probands affected by true
Brugada syndrome) [6]
ECG, Electrocardiogram; RVOT, right ventricular outflow tract; SCN5A, sodium channel voltage-
gated type-V alpha subunit.
Adapted from Anselm DD, Baranchuk A. Brugada phenocopy in the context of pulmonary
embolism. Int J Cardiol 2013;168:560.[27]

ECG manifestations lies in malfunction of other ion channels. It may be found

that BrP and BrS fall within the same clinical spectrum of disease or that they
are different entities altogether.
The international registry (www.brugadaphenocopy.com) is aimed at fur-
thering knowledge on BrP etiology, pathophysiology, and natural history (see
Chapter 7) [28]. At this point, it is unknown whether BrP is a risk factor for
malignant arrhythmias. There have been no studies that have examined the
long-term prognosis of these patients. Questions that remain unanswered in-
clude whether development of BrP predisposes patients to malignant arrhyth-
mias under certain clinical conditions, or whether a patient that develops BrP in
the context of one etiology is at risk of developing BrP in another etiology. The
international database will aid in answering these questions through collating
patients, identifying patterns, and assessing the long-term morbidity and mor-
tality of these patients through longitudinal follow-up. With further emergence
of the concept and more widespread use of the term “Brugada phenocopy” in
the literature, the number of cases in the database has continued to grow. To
facilitate future research on the topic, it is important to use the eponym cre-
ated to group this series of conditions presenting with Brugada ECG patterns:
“Brugada phenocopy.”

REFERENCES
[1] Baranchuk A, Nguyen T, Ryu MH, et al. Brugada phenocopy: new terminology and proposed
classification. Ann Noninvasive Electrocardiol 2012;17:299–314.
[2] Anselm DD, Gottschalk BH, Baranchuk A. Brugada phenocopies: consideration of morpho-
logic criteria and early findings from an international registry. Can J Cardiol 2014;30:1511–5.
18 Brugada Phenocopy

[3] Gottschalk BH, Anselm DD, Brugada J, et al. Expert cardiologists cannot distinguish be-
tween Brugada phenocopy and Brugada syndrome electrocardiogram patterns. Europace
2016;18:1095–100.
[4] Gottschalk BH, Garcia-Niebla J, Anselm DD, Jaidka A, De Luna AB, Baranchuk A. New
methodologies for measuring Brugada ECG patterns cannot differentiate the ECG pattern of
Brugada syndrome from Brugada phenocopy. J Electrocardiol 2016;49:187–91.
[5] Postema PG, Wolpert C, Amin AS, et al. Drugs and Brugada syndrome patients: review of
the literature, recommendations, and an up-to-date website (www.brugadadrugs.org). Heart
Rhythm 2009;6:1335–41.
[6] Probst V, Wilde AA, Barc J, et al. SCN5A mutations and the role of genetic background in the
pathophysiology of Brugada syndrome. Circ Cardiovasc Genet 2009;2:552–7.
[7] Bayés de Luna A, Brugada J, Baranchuk A, et al. Current electrocardiographic criteria for
diagnosis of Brugada pattern: a consensus report. J Electrocardiol 2012;45:433–42.
[8] Gottschalk B, Anselm DD, Baranchuk A. Brugada phenocopy: morphological classification
and importance of provocative testing. Ann Noninvasive Electrocardiol 2014;19:604–5.
[9] Bayes de Luna A, Brugada J, Baranchuk A, et al. Current electrocardiographic criteria for
diagnosis of Brugada pattern: a consensus report. J Electrocardiol 2012;45:433–42.
[10] Anselm DD, Baranchuk A. Brugada phenocopy: redefinition and updated classification. Am J
Cardiol 2013;111:453.
[11] Anselm DD, Baranchuk A. Brugada phenocopy emerging as a new concept. Rev Esp Cardiol
(Engl Ed) 2013;66:755.
[12] Dendramis G, Petrina SM, Baranchuk A. Not all ST-segment elevations are myocardial infarc-
tion: hyperkalemia and Brugada phenocopy. Am J Emerg Med 2017;35:662.e1–2.
[13] Hunuk A, Hunuk B, Kusken O, Onur OE. Brugada phenocopy induced by electrolyte disorder:
a transient electrocardiographic sign. Ann Noninvasive Electrocardiol 2016;21:429–32.
[14] Recasens L, Merono O, Ribas N. Hyperkalemia mimicking a pattern of Brugada syndrome.
Rev Esp Cardiol (Engl Ed) 2013;66:309.
[15] Agrawal Y, Aggarwal S, Kalavakunta JK, Gupta V. All that looks like “Brugada” is not
“Brugada”: case series of Brugada phenocopy caused by hyponatremia. J Saudi Heart Assoc
2016;28:274–7.
[16] Genaro NR, Anselm DD, Cervino N, et al. Brugada phenocopy clinical reproducibility dem-
onstrated by recurrent hypokalemia. Ann Noninvasive Electrocardiol 2014;19:387–90.
[17] Meloche J, Gottschalk BH, Boles U, LaHaye S, Baranchuk A. Hypophosphatemia as a novel
etiology of Brugada phenocopy. Int J Cardiol 2016;208:70–1.
[18] Gottschalk BH, Anselm DD, Baranchuk A. Phosphine poisoning is emerging as an important
cause of Brugada phenocopy. PACE 2016;39:202–3.
[19] Lodde B, Lucas D, Letort JM, Jegaden D, Pougnet R, Dewitte JD. Acute phosphine poison-
ing on board a bulk carrier: analysis of factors leading to a fatal case. J Occup Med Toxicol
2015;10:10.
[20] Prabhu MA, Agustinus R, Shenthar J. Suicidal zinc phosphide poisoning unmasking Brugada
syndrome and triggering near fatal ventricular arrhythmia. PACE 2016;39:198–201.
[21] Rangaraj R, Moorthy N, Patil SS, Manjunath C. Brugada-type electrocardiographic pattern
induced by electrocution. Indian Pacing Electrophysiol J 2009;9:56–9.
[22] Wang JG, McIntyre WF, Kong W, Baranchuk A. Electrocution-induced Brugada pheno-
copy. Int J Cardiol 2012;160:e35–7.
[23] Labadet C, Gottschalk BH, Rivero M, et al. Brugada phenocopy in the context of intracranial
hemorrhage. Int J Cardiol 2014;177:e156–7.
 Definition, Diagnosis, and Differentiation Chapter | 2 19

[24] Anselm DD, Pérez-Riera A, Femenia F, Baranchuk A. Brugada phenocopy in a patient with
surgically repaired pentalogy of Fallot. Rev Iberoam Arritmol 2012;3:20–4.
[25] Wilde AA, Antzelevitch C, Borggrefe M, et al. Proposed diagnostic criteria for the Brugada
syndrome: consensus report. Circulation 2002;106:2514–9.
[26] Antzelevitch C, Brugada P, Borggrefe M, et al. Brugada syndrome: report of the second con-
sensus conference: endorsed by the Heart Rhythm Society and the European Heart Rhythm
Association. Circulation 2005;111:659–70.
[27] Anselm DD, Baranchuk A. Brugada phenocopy in the context of pulmonary embolism. Int J
Cardiol 2013;168:560.
[28] Brugada phenocopy international registry and online educational portal, www.brugadapheno-
copy.com; 2014 [accessed January 2017].