INTRODUCTION — The vast majority of cases of sudden cardiac arrest (SCA) and sudden cardiac death (SCD) are caused by ventricular tachyarrhythmias, with most of these associated with structural heart disease, particularly coronary heart disease. SCA in the apparently normal heart is an uncommon occurrence, accounting for only 5 to 10 percent of SCA cases. (See "Pathophysiology and etiology of sudden cardiac arrest".)
Some causes of SCA in patients with apparently normal hearts have been identified and include:
●Brugada syndrome
●Congenital long QT syndrome (LQTS) (see "Congenital long QT syndrome: Epidemiology and clinical manifestations")
●Acquired LQTS with polymorphic ventricular tachycardia (VT) (see "Acquired long QT syndrome: Definitions, pathophysiology, and causes")
●Catecholaminergic polymorphic VT (see "Catecholaminergic polymorphic ventricular tachycardia")
●Idiopathic VT (see "Ventricular tachycardia in the absence of apparent structural heart disease")
●Idiopathic ventricular fibrillation
●Short QT syndrome (see "Short QT syndrome")
●Commotio cordis (see "Commotio cordis")
The clinical manifestations, evaluation, and diagnosis of the Brugada syndrome will be reviewed here. The epidemiology, pathogenesis, management, and prognosis of the Brugada syndrome, along with a discussion of the other causes of SCA in apparently normal hearts, are discussed elsewhere. (See "Approach to sudden cardiac arrest in the absence of apparent structural heart disease" and "Brugada syndrome: Epidemiology and pathogenesis" and "Brugada syndrome: Prognosis, management, and approach to screening".)
CLINICAL PRESENTATION — The Brugada syndrome combines the typical electrocardiogram (ECG) findings of the Brugada ECG pattern with a presentation suggesting ventricular arrhythmias. Most clinical manifestations of the Brugada syndrome are related to life-threatening ventricular arrhythmias [1,2].
●Sudden cardiac arrest (SCA), resulting from a ventricular tachyarrhythmia, may be the initial presentation of Brugada syndrome in as many as one-third of patients. Most often the presenting arrhythmia is ventricular fibrillation (VF) or polymorphic ventricular tachycardia (VT).
●Patients may also present with an episode of syncope with features suggestive of a tachyarrhythmic cause of the syncope.
●Palpitations related to ventricular tachyarrhythmia are not common in the Brugada syndrome, but patients may present with palpitations related to atrial fibrillation, which is associated with Brugada syndrome and may be the first presentation of the disease [3].
●Nocturnal agonal respiration is also described and is part of the diagnostic criteria.
Patients with the Brugada pattern ECG without any apparent symptoms are typically identified when an ECG is performed for another reason (eg, pre-operative evaluation, annual physical examination, etc) or as part of the screening of first-degree relatives of a Brugada proband.
Definition of Brugada pattern versus Brugada syndrome — Two terms, distinguished by the presence or absence of symptoms, have been used to describe patients with the typical ECG findings of a pseudo-right bundle branch block and persistent ST segment elevation in leads V1 to V2 (waveform 1):
●Patients with typical ECG features who are asymptomatic and have no other clinical criteria are said to have the Brugada pattern (sometimes referred to as Brugada phenocopies).
●Patients with typical ECG features who have experienced sudden cardiac death or a sustained ventricular tachyarrhythmia, or who have one or more of the other associated clinical criteria, are said to have the Brugada syndrome. Patients with ventricular premature beats or nonsustained VT, however, are generally not considered to have Brugada syndrome but only the Brugada pattern.
Persons with either the Brugada pattern or the Brugada syndrome can have identical findings on the surface ECG. (See 'ECG findings' below.)
Sudden cardiac arrest and syncope — SCA and syncope resulting from ventricular tachyarrhythmias are the most significant clinical manifestations of Brugada syndrome.
SCA may be the initial presentation of Brugada syndrome in as many as one-third of patients. Arrhythmic events generally occur between the ages 22 and 65 and are more common at night than in the day and during sleep than while awake [4,5]. In contrast to patients with ischemic or nonischemic cardiomyopathy, in whom monomorphic VT is most common, the majority of patients with Brugada syndrome who present with SCA or syncope have VF or polymorphic VT [6]. (See "Brugada syndrome: Epidemiology and pathogenesis", section on 'Age at diagnosis'.)
SCA in patients with Brugada syndrome is usually not related to exercise [7]. Stored electrograms from implantable cardioverter-defibrillators (ICDs) have shown that frequent spontaneous premature ventricular beats, which are identical in morphology to those that initiate VF, are often seen before the onset of the arrhythmia [8]. (See 'Differential diagnosis for VT or sudden death with a structurally normal heart' below.)
Syncope is a common finding in patients with Brugada syndrome, occurring in 28 percent of patients in one study, though it should be noted that in this study, 30 percent of the episodes of syncope were due to nonarrhythmic causes (eg, neurocardiogenic), and these patients had a benign prognosis [9].
Atrial fibrillation — Patients with Brugada syndrome are at increased risk of atrial arrhythmias, most notably atrial fibrillation (AF) [10-13]. The incidence of AF is 10 to 20 percent in patients with Brugada syndrome, and the presence of AF has been associated with increased disease severity and a higher risk of VF [10,12]. (See "Brugada syndrome: Prognosis, management, and approach to screening", section on 'Prognostic factors' and "Mechanisms of atrial fibrillation".)
As examples:
●Among 59 patients with Brugada pattern ECGs and 31 matched controls who were followed for an average of three years, AF occurred in 12 (20 percent) patients with Brugada pattern ECGs but in none of the control subjects [10].
●Among 611 patients with Brugada pattern ECG, the diagnosis of AF preceded the diagnosis of Brugada pattern ECG in 35 (5.7 percent) [3]. The diagnosis of Brugada pattern ECG was made in 11 patients after initiation of a class 1c antiarrhythmic agent (table 1) for treatment of AF.
These findings are consistent with a diffuse myocardial nature of the sodium channel abnormality involving both the atria and the ventricles.
Nocturnal agonal respiration — SCA is more common at night in patients with the Brugada syndrome, and sleep disordered breathing appears to be more commonly seen in patients with Brugada syndrome [14]. (See 'Sudden cardiac arrest and syncope' above.)
A pattern of nocturnal agonal respiration with gasping breaths during sleep has been reported and may represent aborted cardiac arrhythmias. This is generally considered an ominous symptom that should be considered the equivalent of syncope or ventricular arrhythmias when evaluating the patient using diagnostic criteria. (See 'Diagnosis' below.)
Sudden unexpected nocturnal death syndrome — A sudden unexpected nocturnal death syndrome (SUNDS, also called sudden unexpected death syndrome or SUDS) has been described in young, apparently healthy males from Southeast Asia; this syndrome has several names including lai tai (death during sleep) in Thailand, bangungut (to rise and moan in sleep followed by death) in the Philippines, and pokkuri (unexpected sudden cardiac death at night) in Japan [15-17].
A low serum potassium level may contribute to SCA in these patients [18]. It has been suggested that a high carbohydrate meal may precipitate SCA, perhaps by increasing the secretion of insulin which drives extracellular potassium into cells.
A relationship to Brugada syndrome was initially suggested by the observation that a majority of patients with SUNDS have the ECG manifestations of Brugada syndrome [17]. This association was confirmed by the finding that these patients have mutations in the same cardiac sodium channel gene, SCN5A, that is abnormal in Brugada syndrome [19]. (See "Brugada syndrome: Epidemiology and pathogenesis".)
Based upon these observations, it has been concluded that SUNDS and Brugada syndrome are phenotypically, genetically, and functionally the same disorder [18,19]. Thus, the management of these patients should be the same as that for classic Brugada syndrome. (See "Brugada syndrome: Prognosis, management, and approach to screening", section on 'Treatment'.)
Impact of age on event rates — While the Brugada syndrome is rarely diagnosed in children, the clinical features of Brugada syndrome in childhood were illustrated in a cohort of 30 children (mean age 8 years) diagnosed at 13 referral centers in Europe [20]. While the majority of children were identified based on family screening (17 of 30), 10 patients had prior unexplained syncope and 1 presented with aborted sudden cardiac death.
Repeat ajmaline challenge following the development of puberty (in patients with a negative result prior to puberty) has been shown to unmask the Brugada ECG pattern in asymptomatic relatives of Brugada syndrome patients [21]. Because the data are limited, the optimal approach to the management of children with Brugada pattern or Brugada syndrome is not known. (See 'Drug challenge' below and "Brugada syndrome: Prognosis, management, and approach to screening", section on 'Treatment'.)
In the largest international multicenter registry (SABRUS) of patients with Brugada syndrome with a documented first arrhythmic event, either at the time of aborted cardiac arrest (n = 426) or after prophylactic ICD implantation (n = 252), the majority (94.2 percent) of the patients were 16 to 70 years old at the time of arrhythmic event. Pediatric (<16 years) and patients >70 years of age comprised 4.3 and 1.5 percent, respectively, suggesting age cutoffs that may be clinically relevant for decision making. Peak arrhythmic event rate occurred between 38 and 48 years (mean 41.9±14.8; range 0.27 to 84 years). In adult patients (≥16 years), women experienced arrhythmic events 6.5 years later than men [22]. In a separate report from the SABRUS cohort, which included 57 patients age ≤20 years, pediatric patients (age ≤12 years) were significantly more likely than adolescents (age 13 to 20 years) to be female (42 versus 13 percent), have a spontaneous type I Brugada ECG pattern (81 versus 52 percent), and to have fever associated with the arrhythmic event (54 versus 7 percent) [23]. Pediatric patients tended to have recurrent events earlier than adolescent patients and these events tended to be associated with fever.
ECG findings — Persons with Brugada pattern findings on a surface ECG have some form of a pseudo-right bundle branch block and persistent ST segment elevation in leads V1 to V2 (waveform 1) [24].
Type 1 versus Type 2 — While three different patterns of ST elevation were initially described and were used in clinical practice for years, subsequent consensus is that there are two distinct patterns of ST elevation (figure 1 and table 2) [18,25,26].
●In the type 1 Brugada ECG pattern, the elevated ST segment (≥2 mm) descends with an upward convexity to an inverted T wave (figure 1). This is referred to as the "coved type" Brugada pattern.
●In the type 2 Brugada ECG pattern (combined from the original designation of types 2 and 3 patterns), the ST segment has a "saddle back" ST-T wave configuration, in which the elevated ST segment descends toward the baseline, then rises again to an upright or biphasic T wave (figure 1).
Moving the right precordial chest leads up to the second or third intercostal space or using bipolar chest leads may increase the sensitivity of detecting these abnormalities and should be performed when there is doubt about the diagnosis [18,27,28]. In a study of 98 men with a family member with a type I Brugada pattern ECG, those with a type I Brugada pattern ECG only in high chest leads had a similar rate of cardiac events during >1 year of follow-up as those with type 1 Brugada pattern ECG with standard positioning of chest leads [29]. However, the incidence of false-positive results needs to be better defined in larger studies.
The widened S wave in left lateral leads that is characteristic of RBBB (waveform 2) is absent in most patients with Brugada pattern ECGs. This observation suggests that there is a high takeoff of the ST segment in the right precordium (ie, a "J" wave rather than a true RBBB) due to abnormal repolarization in the RVOT [30]. Other ECG findings to distinguish Brugada pattern ECGs from incomplete RBBB, related to the ST segment angle, have also been reported [31,32]. (See "Brugada syndrome: Epidemiology and pathogenesis", section on 'Pathogenesis'.)
QT interval prolongation may be seen in the right precordial leads [33]. The degree of prolongation is usually modest, but some patients have genetic abnormalities that cause both Brugada pattern ECG and long QT syndrome [34-36]. (See "Brugada syndrome: Epidemiology and pathogenesis", section on 'Related disorders with SCN mutations'.)
Variation of ECG findings over time — In some patients, the characteristic ECG changes of the Brugada pattern are transient or variable over time.
●In one series of 43 patients with Brugada pattern ECGs, in whom 310 ECGs were obtained over a median follow-up of 18 months, the following findings were noted [37]:
•Among 15 patients with a spontaneous Brugada type 1 ECG at presentation, 14 had at least one non-diagnostic (ie, not type 1) ECG during follow-up.
•Among 28 patients whose initial ECG was non-diagnostic, eight developed characteristic Brugada type 1 ECG abnormalities during follow-up.
●In a cohort of 251 patients with Brugada pattern ECG (including 30 percent with spontaneous Brugada type 1 ECG and 70 percent with drug-induced Brugada type 1 ECG) who underwent 12-lead ambulatory monitoring for 24 hours, the Brugada type 1 ECG pattern was frequently intermittent or absent during the 24-hour monitoring period [38].
Thus, fluctuations in the Brugada ECG pattern over time appear to be common and may affect the results of screening ECGs performed in first degree relatives. (See "Brugada syndrome: Prognosis, management, and approach to screening", section on 'Frequency of repeat screening'.)
Provoking factors
Fever — Fever can be a trigger for both induction of Brugada pattern ECG abnormalities and cardiac arrest among persons known to have Brugada pattern ECG or Brugada syndrome. Animal models have helped elucidate how hyperthermia causes changes in sodium current function. A reduction in sodium current results in changes to the action potential predisposing to VF [39].
●In a study of 402 febrile emergency department patients and 909 controls, type I Brugada pattern ECG changes were 20 times more common in febrile patients (2 versus 0.1 percent) [40]. None of these patients had events in 30 months of follow-up, but this study suggested that fever-induced Brugada pattern may be more prevalent than generally realized.
●In a single-center retrospective review of 111 patients with Brugada syndrome, 22 patients had cardiac arrest, and 4 of these patients (18 percent) had a preceding fever [41]. In a subset of 24 of the 111 patients with ECGs recorded during both fever and normothermia, fever was associated with prolonged QRS and QT intervals and worsening ST elevation (waveform 3). Fever was present in 4 of 22 patients with cardiac arrest.
In the Survey on Arrhythmic Events in Brugada Syndrome (SABRUS), an international multicenter registry that includes 678 patients with a documented arrhythmic event, 35 of 588 patients (6 percent) had an arrhythmic event during febrile illness [42]. Most of the 35 patients were male (80 percent), White individuals (83 percent), and proband (70 percent). The pediatric population displayed the highest rate of fever-related arrhythmic event (age <16 years), with a disproportionally higher event rate in the very young (age 0 to 5 years, 65 percent).
Medications, metabolic disturbances, and toxins — The characteristic Brugada pattern ECG abnormalities may be exposed by a sodium channel blocker, such as flecainide, ajmaline, or procainamide, thereby identifying those at risk (table 3) [4,18,43-45]. The known properties of some of these agents allows them to be utilized as part of a drug challenge to confirm the diagnosis. (See 'Drug challenge' below.)
Other medications and toxins that can unmask or modulate the Brugada ECG pattern are beta blockers, tricyclic or tetracyclic antidepressants, lithium, local anesthetics, and alcohol and cocaine toxicity (table 3) [18,46,47]. A website has been established that identifies drugs that have been associated with adverse events in BS patients [48]. Additionally, patients with metabolic disturbances (eg, severe hyperkalemia) may present with Brugada pattern ECG which is reversible following correction of the underlying metabolic disturbance [49]. (See "Brugada syndrome: Epidemiology and pathogenesis", section on 'Cocaine abuse' and "Brugada syndrome: Epidemiology and pathogenesis", section on 'Psychotropic drugs'.)
The clinical significance of drug-provoked ECG changes in the absence of symptoms, family history of BS, or family with Brugada ECG is undetermined.
DIAGNOSIS — The diagnosis of Brugada syndrome is most commonly made following a clinically significant event (ie, syncope, sudden cardiac death) in which the patient has the typical Brugada pattern ECG findings. However, some patients may be diagnosed based on the presence of ECG findings and relevant family history of sudden cardiac death or Brugada ECG patterns.
The diagnosis of Brugada syndrome can be challenging, however, requiring a high degree of clinical suspicion. Both Brugada pattern ECG findings and clinical features are required to make the diagnosis, as Brugada syndrome would not be diagnosed in the setting of ventricular arrhythmias and/or sudden cardiac death in the absence of the typical Brugada pattern ECG manifestations [50,51]. Conversely, the appearance of typical ECG changes alone without other clinical manifestations is considered to represent the Brugada ECG pattern but not the Brugada syndrome.
Because of the clinical variability in presentation and the different ECG manifestations which can be seen in the Brugada syndrome, diagnostic criteria have been proposed by professional societies from both Europe and North America [1,18,25].
2013 HRS/EHRA/APHRS criteria — In 2013, three major professional societies, the Heart Rhythm Society (HRS), the European Heart Rhythm Association (EHRA), and the Asia Pacific Heart Rhythm Society (APHRS), jointly issued an expert consensus statement on inherited arrhythmia syndromes, which included updated diagnostic criteria for Brugada syndrome [1].
●The 2013 consensus statement suggested that Brugada syndrome should be "definitively diagnosed" with symptoms and the presence of type I Brugada pattern ECG changes in at least one right precordial lead (specifically V1 or V2), either spontaneously or following drug challenge with a sodium channel blocker, using standard or superior ECG lead placement. (See 'Drug challenge' below.)
●For a patient with type I Brugada pattern ECG findings who is otherwise asymptomatic, clinical findings which would support the diagnosis of Brugada syndrome include the following:
•Presence of first degree AV block and left axis deviation on the ECG
•Atrial fibrillation (see 'Atrial fibrillation' above)
•Late potentials seen on signal-averaged ECG (see "Signal-averaged electrocardiogram: Overview of technical aspects and clinical applications")
•Fragmented QRS complex
•ST-T wave alternans with spontaneous ventricular premature beats in a left bundle branch blocker pattern on prolonged ECG recording
•Ventricular refractory period <200 milliseconds and HV interval >60 milliseconds during invasive electrophysiology (EP) study
•Absence of structural heart disease, including myocardial ischemia
2005 HRS/EHRA criteria — In a 2005 report of the second consensus conference on the Brugada syndrome, published jointly by the HRS and the EHRA, diagnostic criteria were proposed for both type 1 and type 2 Brugada ECG patterns. We agree with the 2013 HRS/EHRA/APHRS consensus statement which updated the 2005 criteria, but the original criteria continue to be frequently cited in clinical practice and more specifically define criteria to diagnose Brugada Syndrome.
Type 1 — The 2005 consensus conference proposed that Brugada syndrome should be strongly considered in patients who meet the following criteria [18]:
●Appearance of type 1 ST segment elevation (coved type) (figure 1) in more than one right precordial lead (V1-V2) in the presence or absence of a sodium channel blocker, plus at least one of the following:
•Documented ventricular fibrillation (VF)
•Polymorphic VT
•Family history of sudden cardiac death at less than 45 years of age
•Family history of type 1 Brugada pattern ECG changes
•Inducible VT during EP study
•Unexplained syncope suggestive of a tachyarrhythmia
•Nocturnal agonal respiration
Type 2 — The 2005 consensus conference proposed that Brugada syndrome should be strongly considered in patients with a type 2 Brugada ECG who meet both of the following criteria [18]:
●Appearance of type 2 ST segment elevation (saddle-back type) (figure 1) in more than one right precordial lead (V1-V2) under baseline conditions, with conversion to type 1 following challenge with a sodium channel blocker, plus at least one of the following:
•Documented VF
•Polymorphic VT
•Family history of sudden cardiac death at less than 45 years of age
•Family history of type 1 Brugada pattern ECG changes
•Inducible VT during EP study
•Unexplained syncope suggestive of a tachyarrhythmia
•Nocturnal agonal respiration
The utility of lead V3 and the necessity of having more than one lead positive in the diagnosis of Brugada syndrome have been called into question by a study of 186 patients with spontaneous or drug-induced type 1 Brugada ECGs [52]. Among 376 ECGs, lead V3 provided no additional diagnostic information in any patient, and patients with ECGs with only one lead with a diagnostic pattern had similar outcomes to patients with 2 or 3 diagnostic leads. Therefore, current criteria have been revised to include only leads V1 and V2 in diagnosis.
EVALUATION AND RISK STRATIFICATION — Once the diagnosis of Brugada syndrome is suspected based on the clinical presentation and ECG findings, additional evaluation may be required to confirm the diagnosis of Brugada syndrome and to provide an estimate of risk of ventricular arrhythmias and sudden cardiac death in the individual patient. In general, all additional diagnostic testing should be performed following consultation with an electrophysiologist or a general cardiologist with specific training and expertise in the diagnosis and management of the Brugada syndrome [53].
Our approach to evaluation and risk stratification — Our approach to the evaluation and risk stratification of patients with Brugada pattern ECG finding (waveform 1) depends in large part on the presence or absence of symptoms:
●All patients with suspected Brugada syndrome, based on the combination of symptoms and typical Brugada pattern ECG changes (either type 1 or type 2), require an evaluation to exclude underlying structural heart disease (algorithm 1). This evaluation should include cardiac imaging (with echocardiography and, in selected cases, cardiac magnetic resonance imaging) and cardiac stress testing.
•If the evaluation reveals structural heart disease or myocardial ischemia suggesting an alternative diagnosis, patients should undergo any relevant additional testing and treatment as directed by the suspected alternative diagnosis.
•If the evaluation does not reveal structural heart disease or myocardial ischemia, and the patient has spontaneous type 1 Brugada pattern ECG changes, Brugada syndrome is diagnosed and patients should be treated accordingly.
•If the evaluation does not reveal structural heart disease or myocardial ischemia, and the patient has spontaneous type 2 Brugada pattern ECG changes, the patient should undergo a drug challenge using a sodium channel blocker in an attempt to elicit the type 1 Brugada ECG pattern. (See 'Drug challenge' below.)
●Patients with only a Brugada pattern ECG who are entirely asymptomatic do not meet the criteria for Brugada syndrome based on ECG findings alone. The following are components of the evaluation of an asymptomatic patient with a Brugada pattern ECG:
•Comprehensive family history looking for first-degree relatives with Brugada syndrome, unexplained sudden cardiac death, or unexplained syncope.
•Cardiac imaging with echocardiography and, in selected cases, cardiac magnetic resonance imaging. (See 'Testing for underlying heart disease' below.)
•Drug challenge – Patients with spontaneous type 1 Brugada pattern ECG findings should not undergo drug challenge; however, a drug challenge is helpful for risk stratification in some patients with a type 2 Brugada pattern ECG. (See 'Drug challenge' below.)
-For asymptomatic patients whose resting ECG shows the type 2 Brugada pattern and who have a family history of sudden cardiac death at less than 45 years of age and/or a family history of type 1 Brugada pattern ECG changes, we proceed with a drug challenge.
-For asymptomatic patients whose resting ECG shows the type 2 Brugada pattern and who have no known family history of sudden cardiac death, we do not recommend a drug challenge.
•Signal-averaged ECG is not performed in most patients, but it can be helpful when there is a high suspicion of Brugada syndrome in spite of negative or equivocal testing. Additionally, signal-averaged ECG may be helpful in identifying a higher risk subset of patients [54,55]. (See 'Signal-averaged ECG' below.)
•The majority of studies do not support universal invasive electrophysiology (EP) testing, and our experts do not recommend EP testing in asymptomatic patients in most circumstances. However, invasive EP testing is an option in asymptomatic patients with a type 1 Brugada pattern ECG who require additional risk stratification, such as when there is an unclear history of syncope or a high risk profession. (See 'Electrophysiology testing' below.)
•Genetic testing – Genetic testing for a mutation in the SCN5A gene should be performed in asymptomatic patients with a Brugada pattern ECG only when a definitive mutation has been identified within the family proband. (See 'Genetic testing' below and "Brugada syndrome: Prognosis, management, and approach to screening", section on 'Screening of first-degree relatives'.)
●In general, all additional diagnostic testing should be performed following consultation with an electrophysiologist or a general cardiologist with specific training and expertise in the diagnosis and management of the Brugada syndrome.
Testing for underlying heart disease — All patients with suspected Brugada syndrome require additional testing to exclude underlying structural heart disease, and many may require testing to exclude myocardial ischemia. This typically includes an echocardiogram and cardiac stress testing, although some centers may perform cardiac magnetic resonance imaging in lieu of echocardiography (or in follow-up if the echocardiogram is of suboptimal technical quality).
Brugada syndrome is not associated with structural heart disease. Standard cardiac testing, including cardiac imaging (with echocardiography and/or cardiac magnetic resonance imaging) and cardiac stress testing, often reveal no abnormalities to suggest an alternative diagnosis.
Patients with spontaneous type 1 Brugada pattern ECGs were found to have significant enlargement of the right ventricular outflow tract on cardiac MRI (as well as mildly lower left and right ventricular ejection fractions) compared with patients with drug-induced type 1 Brugada pattern ECGs and controls. The differences were not large enough to aid in diagnosis but provided further evidence of subtle structural abnormalities [56].
Drug challenge — Among patients with the type 2 Brugada ECG pattern, the type 1 Brugada ECG pattern can occasionally be unmasked by sodium channel blockers (eg, flecainide, procainamide, ajmaline, pilsicainide) (waveform 4 and waveform 5) [18,43-45]. The importance of unmasking the type 1 Brugada ECG pattern relates to its relevance in confirming the diagnosis of Brugada syndrome in symptomatic patients, and for risk stratification purposes in asymptomatic patients [57]. However, not all patients with a type 2 Brugada ECG need to undergo drug challenge. In particular:
●Patients with spontaneous type 1 Brugada pattern ECG findings, with or without symptoms, should not undergo a drug challenge.
●For symptomatic patients whose resting ECG shows the type 2 Brugada pattern, our experts feel that drug challenge is not always necessary. Patients who have documented ventricular fibrillation (VF), polymorphic ventricular tachycardia (VT), unexplained syncope strongly suggestive of a tachyarrhythmia, or nocturnal agonal respiration in the setting of a type 2 Brugada pattern ECG should receive an implantable cardioverter-defibrillator (ICD) regardless of the results of drug testing. However, drug testing may be used in these patients to establish a diagnosis, which may guide future management and prompt risk stratification of family members. (See 'Diagnosis' above and "Brugada syndrome: Prognosis, management, and approach to screening", section on 'Treatment'.)
●For asymptomatic patients whose resting ECG shows the type 2 Brugada pattern and who have a family history of sudden cardiac death at less than 45 years of age and/or a family history of type 1 Brugada pattern ECG changes, we proceed with a drug challenge.
●For asymptomatic patients whose resting ECG shows the type 2 Brugada pattern and who have no known family history of sudden cardiac death, we do not recommend a drug challenge.
While drug challenge can be helpful when positive, the reported sensitivity of pharmacologic challenge with these drugs has been variable, ranging from as low as 15 percent up to 100 percent [44,58]. The duration of monitoring following the administration of the challenge agent is likely related to the sensitivity of the test.
In a study of 245 patients with Brugada syndrome who underwent sodium channel blocker challenge with pilsicainide (181 patients with spontaneous type 1 ECG, 64 patients with non-type 1 ECG), induced ventricular arrhythmias and ST-segment augmentation were associated with an increased risk of the development of VT/VF events during a mean follow-up of 113 months [59].
Drug challenge procedure — One of several sodium channel blocking drugs can be used for the drug challenge [60]. Testing should be performed in a closely monitored setting on telemetry with a code cart readily accessible, as drug challenge may precipitate ventricular arrhythmias in some patients. Recommended doses for the different drugs include [18]:
●Flecainide – 2 mg/kg over 10 minutes intravenously or 400 mg orally
●Procainamide – 10 mg/kg over 10 minutes intravenously
●Ajmaline – 1 mg/kg over 5 minutes intravenously
●Pilsicainide – 1 mg/kg over 10 minutes intravenously
The choice of one agent versus another is typically site specific, based upon availability, as these drugs have never been compared head-to-head in the same patients, so there is no direct evidence that one is more effective than the others for making the diagnosis of Brugada syndrome. One non-randomized study of 425 patients referred for drug challenge, however, suggested that among patients challenged with ajmaline (n = 331) or procainamide (n = 94), those receiving ajmaline were significantly more likely to develop a type I Brugada ECG pattern (26 versus 4 percent, respectively) [61].
Indications for termination of the drug challenge include:
●Development of a diagnostic type 1 Brugada ECG pattern
●≥2 mm increase in ST segment elevation in patients with a type 2 Brugada ECG pattern
●Development of ventricular premature beats or other arrhythmias
●Widening of the QRS ≥30 percent above baseline
Sustained ventricular arrhythmias following drug challenge have been reported in 1 to 2 percent of drug challenges and with all of the drugs used for the challenge [44,62-66].
●In the largest cohort reported to date of 503 patients with unmasking of a Brugada pattern ECG following ajmaline administration, nine patients (two percent) developed sustained ventricular arrhythmias requiring defibrillation [64].
●In a systematic review of 16 studies of ajmaline challenge, totalling 3515 tests, 33 patients (0.9 percent) developed VT or VF [65].
●Among 672 asymptomatic family members of probands who underwent screening with drug challenge, VT or VF developed in 10 patients (1.5 percent) [66].
In a single-center study of 59 patients who underwent flecainide challenge and had continuous ECG monitoring for 30 minutes followed by an ECG at 90 minutes post-flecainide, significantly more patients developed a type I ECG pattern at 90 minutes (11 of 59 patients [19 percent] compared with only 12 percent within the first 30 minutes and 7 percent within the first 10 minutes) [67]. A drug challenge should only be performed by clinicians experienced in the administration of sodium channel blocking drugs and interpretation of ECGs. When performing a drug challenge, the patient should have continuous ECG monitoring, typically for 30 minutes following intravenous drug administration and up to four hours or longer if oral flecainide is used for the drug challenge.
Signal-averaged ECG — Signal-averaged ECG (SAECG) testing may be helpful in identifying patients with Brugada pattern ECG and an increased risk of future arrhythmic events [68]. In a prospective study of 43 patients with Brugada syndrome, the presence of late potentials on signal-averaged ECG was significantly predictive of arrhythmic events. Patients with late potentials had a significantly higher arrhythmic event rate over 34 month follow-up compared with those without late potentials (72.4 versus 14.3 percent) [54]. (See "Signal-averaged electrocardiogram: Overview of technical aspects and clinical applications".)
12-lead ECG — The finding of an S wave in lead 1 ≥0.1 millivolts and ≥40 milliseconds in duration, thought to represent delayed right ventricular outflow tract conduction, may be a strong predictor of sudden death. In a cohort of 347 asymptomatic patients with spontaneous type 1 Brugada pattern ECGs, 32 persons (9 percent) developed VF or sudden cardiac death over a mean follow-up of 4 years [69]. On multivariate analysis only presence of an S wave in lead 1 (hazard ratio [HR] 39.1) and atrial fibrillation (HR 3.7) were independent predictors of sudden death, with the negative predictive value of this finding being nearly 99 percent. This finding has not been confirmed on subsequent studies, and thus should be used solely for risk stratification. However, the strength of this data in a relatively large Brugada cohort suggests that it would be reasonable to consider this in an overall risk stratification of an asymptomatic patient, particularly when absent, since the negative predictive value is quite high.
Electrophysiology testing — Because the available data in asymptomatic patients are conflicting, and the majority of studies do not support EP testing, our experts do not recommend EP testing in asymptomatic patients in most circumstances. Though invasive EP testing in asymptomatic patients for diagnostic and prognostic purposes had been recommended in the 2005 consensus statement on Brugada syndrome, the 2013 HRS/EHRA/APHRS consensus statement concluded that "there is no consensus" regarding the prognostic capability of invasive EP testing, and the 2017 AHA/ACC/HRS guideline states that EP testing "may be considered" as part of risk stratification [1,18,57]. In certain cases, it may be offered to patients for further risk stratification in the presence of equivocal symptoms and may be part of the decision-making process when determining candidacy for ICD placement.
For the majority of asymptomatic patients with Brugada pattern ECG findings, invasive EP testing is not necessary [68,70]. Patients with a Brugada ECG pattern and certain high-risk clinical features (ie, a history of sudden cardiac arrest [SCA], sustained ventricular tachyarrhythmias, or unexplained syncope) have an indication for ICD implantation, so invasive EP testing is unlikely to impact management [4,30,71-74]. (See "Brugada syndrome: Prognosis, management, and approach to screening".)
The role of EP testing in asymptomatic patients remains an area of investigation and debate in which results have been inconsistent.
●Among 547 patients with an ECG diagnostic of type 1 Brugada syndrome and no prior cardiac arrest, invasive EP testing was performed at the discretion of the clinician in 408 patients, 163 of whom had an inducible sustained ventricular arrhythmia [71]. Inducible sustained ventricular tachyarrhythmia during invasive EP testing was a significant predictor of future adverse events.
●Among 369 asymptomatic patients from the FINGER registry who underwent invasive EP testing, inducible sustained ventricular tachyarrhythmia during EP testing showed no independent predictive value for future arrhythmic events [75].
●Among 308 consecutive patients prospectively enrolled in a registry with either spontaneous or induced type I ECG findings and no history of SCA, programmed electrical stimulation was not a predictor of events during follow-up [76]. However, the presence of spontaneous type I ECG, syncope, ventricular effective refractory period <200 milliseconds, and QRS fragmentation were significant predictors of arrhythmia over a median of 34 months.
Additional studies raise questions about the reliability of using EP testing for risk stratification. In a 2017 systematic review performed as part of the 2017 AHA/ACC/HRS guidelines, which included only studies of asymptomatic patients with Brugada ECG findings who had undergone invasive EP testing with programmed ventricular stimulation (6 studies with 1138 patients), 390 patients (34.3 percent) were found to have inducible VT during EP testing [70]. During follow-up, only 25 patients (13 of 390 in the inducible VT group, 12 of 748 in the noninducible group) experienced an arrhythmic event (sustained VT, sudden cardiac death, or appropriate defibrillator therapy), with no significant difference in events between the two groups (odds ratio 2.3 for inducible patients; 95% CI 0.6-8.7). In a 2016 pooled analysis of data from eight nonrandomized studies including 1312 patients with type 1 Brugada pattern ECGs and no prior documented ventricular arrhythmias who had undergone invasive EP testing, patients with inducible ventricular arrhythmias had a significantly greater risk of future SCA or appropriate ICD therapy (40 of 65 events; adjusted HR 2.7; 95% CI 1.4-4.9) [77]. However, over one-third of the events (25 of 65) occurred in patients who were noninducible.
Invasive EP testing combined with myocardial substrate electroanatomic mapping may be a way to more accurately predict inducible arrhythmias. In a single-center cohort of 191 patients with Brugada ECG pattern, including 88 (46 percent) who were symptomatic, all patients underwent invasive EP testing with substrate mapping enhanced by ajmaline challenge [78]. Only 53 percent of patients were inducible prior to ajmaline challenge (66 percent of symptomatic patients compared with only 43 percent of asymptomatic patients); arrhythmogenic substrate area >4cm2 on substrate mapping was highly correlated with VT/VF inducibility during invasive EP testing. Ablation of the arrhythmogenic substrate resulted in all patients being noninducible; however, no long-term clinical follow-up was reported. While potentially interesting as a way to further risk stratify, and potentially treat, patients with Brugada syndrome, further studies confirming these findings, ideally with mid- or long-term clinical follow-up, would be required prior to changing clinical practice.
The small number of events limits the ability to detect a meaningful difference in events between patients with inducible VT during EP testing compared with noninducible patients. However, because the majority of data do not support EP testing, we do not perform EP testing in asymptomatic patients in most circumstances. Additionally, the overall low event rate is reassuring and suggests asymptomatic patients with Brugada ECG findings have a low risk of future arrhythmic events.
Genetic testing — We suggest genetic testing for all patients with documented Brugada syndrome ("probands"). If the proband has an identified genetic mutation (ie, genotype positive), we pursue genetic testing in all of the proband's first degree relatives. We do not recommend genetic testing for Brugada pattern ECG probands or their first degree relatives.
Genetic testing for Brugada syndrome, which typically involves sequencing SCN5A, SCN10a, and a number of other identified genes, is commercially available and can be useful in confirming the presence of a mutation in a patient with the suspected diagnosis of Brugada syndrome. We advise that genetic testing for Brugada syndrome be performed in conjunction with specialists who have expertise in this area [79].
In patients with a clinical diagnosis of Brugada syndrome, genetic testing may also allow family screening and risk stratification. However, the genetic and clinical heterogeneity of Brugada syndrome limit the utility of genetic testing, as the absence of a mutation in SCN5A does not exclude Brugada syndrome, and the presence of a mutation in SCN5A does not confirm the diagnosis of Brugada syndrome.
●Only 15 to 30 percent of patients diagnosed with Brugada syndrome have mutations in SCN5A [80,81]. This may reflect variations in the testing procedure since mutations in non-coding regions or alterations in splice sites are not always examined even though they can lead to abnormal sodium channel activity. In addition, there is evidence that mutations in other genes can give rise to this disorder [80]. (See "Brugada syndrome: Epidemiology and pathogenesis", section on 'Non-sodium channel genes'.)
●Not all patients with documented Brugada SCN5A mutations have Brugada syndrome. In one study, the average penetrance among 24 patients in four genotyped families was only 16 percent (one Brugada patient in each family) [58].
●In one study of 415 probands with Brugada syndrome who underwent genetic testing for SCN5A, 60 patients (15 percent) had identified mutations [81]. Patients with SCN5A mutations had higher rates of cardiac arrhythmic events beginning at a younger age (34 versus 42 years in patients without SCN5A mutation).
DIFFERENTIAL DIAGNOSIS
Differential diagnosis of Brugada pattern ECG findings — The differential diagnosis for Brugada pattern ECG changes includes other conditions that result in apparent conduction and ST segment abnormalities in leads V1 to V2 on the ECG. Examples of such conditions include:
●Atypical right bundle branch block (see "Right bundle branch block", section on 'ECG findings and diagnosis')
●Arrhythmogenic right ventricular cardiomyopathy (see 'Brugada ECG pattern in ARVC' below)
●Early repolarization (see "Early repolarization", section on 'ECG findings')
●Acute pericarditis (see "Acute pericarditis: Clinical presentation and diagnosis", section on 'Electrocardiogram')
●Acute myocardial ischemia or infarction (see "Electrocardiogram in the diagnosis of myocardial ischemia and infarction")
●Left ventricular hypertrophy (see "Left ventricular hypertrophy: Clinical findings and ECG diagnosis")
●Pectus excavatum (see "Pectus excavatum: Etiology and evaluation", section on 'Cardiac function')
●Hypothermia (see "ECG tutorial: Miscellaneous diagnoses", section on 'Hypothermia')
Brugada ECG pattern in ARVC — The Brugada pattern on ECG can be seen as an early subclinical manifestation of arrhythmogenic right ventricular cardiomyopathy (ARVC) [72]. ARVC is a genetic disorder, usually autosomal dominant, which primarily involves the right ventricle, as the right ventricular myocardium is typically replaced by fat, with scattered residual myocardial cells and fibrous tissue. (See "Arrhythmogenic right ventricular cardiomyopathy: Pathogenesis and genetics".)
An association between ARVC and the Brugada pattern on ECG is suggested by a report of 96 victims of sudden cardiac death (SCD) who were ≤35 years and had a baseline ECG available [7]. Right precordial ST segment elevation with or without RBBB was present in 13 (14 percent); at autopsy, all but one had ARVC. However, this study was from southern Italy, where ARVC is an important cause of SCD. Furthermore, mutations in SCN5A have not been described in ARVC.
Patients with ARVC often have abnormalities in the right ventricle that can be seen on echocardiography or cardiac magnetic resonance imaging. In contrast, the vast majority of patients with Brugada syndrome do not have apparent structural heart disease on routine imaging studies [18]. (See "Arrhythmogenic right ventricular cardiomyopathy: Diagnostic evaluation and diagnosis", section on 'Diagnostic evaluation'.)
Differential diagnosis for VT or sudden death with a structurally normal heart — Additionally, for patients with clinical manifestations of ventricular tachyarrhythmias (ie, sudden cardiac death, syncope) and no apparent cardiac structural abnormalities, several conditions should be considered along with the Brugada syndrome, including:
●Congenital long QT syndrome (LQTS)
●Acquired LQTS with polymorphic ventricular tachycardia (VT)
●Short QT syndrome
●Catecholaminergic polymorphic VT
●Commotio cordis
●Idiopathic VT (see "Ventricular tachycardia in the absence of apparent structural heart disease")
●Idiopathic ventricular fibrillation (see "Approach to sudden cardiac arrest in the absence of apparent structural heart disease", section on 'Idiopathic VF')
For most conditions in which VT or sudden cardiac death (SCD) occurs with no apparent cardiac structural abnormalities, the clinical scenario and the ECG findings can be used to exclude other conditions. As examples:
●Patients with VT or SCD associated with prolongation of the QT interval are more likely to have LQTS than Brugada syndrome, particularly if the patient has been exposed to medications which may prolong the QT interval. Similarly, patients with VT or SCD whose QT interval is markedly shortened are more likely to have short QT syndrome. (See "Congenital long QT syndrome: Epidemiology and clinical manifestations" and "Acquired long QT syndrome: Definitions, pathophysiology, and causes" and "Short QT syndrome".)
●Patients who experience VT or SCD in the setting of exertion are more likely to have catecholaminergic polymorphic VT than Brugada syndrome, in which symptomatic tachyarrhythmias are more likely to occur at rest. (See "Catecholaminergic polymorphic ventricular tachycardia".)
●Patients with VT or SCD following blunt chest trauma are more likely to have experienced commotio cordis. (See "Commotio cordis".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Inherited arrhythmia syndromes".)
SUMMARY AND RECOMMENDATIONS
●The Brugada syndrome combines the typical electrocardiogram (ECG) findings of the Brugada ECG pattern with a presentation suggesting ventricular arrhythmias. Most clinical manifestations of the Brugada syndrome are related to life-threatening ventricular arrhythmias, most often ventricular fibrillation or polymorphic ventricular tachycardia. Patients may also present with syncope, palpitations, atrial fibrillation, nocturnal agonal respiration, or sudden unexpected nocturnal death. (See 'Clinical presentation' above.)
●Persons with Brugada pattern findings on a surface ECG have some form of a pseudo-right bundle branch block and persistent ST segment elevation in leads V1 to V2 (waveform 1). In some patients, the characteristic ECG changes of the Brugada pattern are transient or variable over time. (See 'ECG findings' above.)
•In the type 1 Brugada ECG pattern, the elevated ST segment (≥2 mm) descends with an upward convexity to an inverted T wave (figure 1). This is referred to as the "coved type" Brugada pattern.
•In the type 2 Brugada ECG pattern (combined from the original designation of types 2 and 3 patterns), the ST segment has a "saddle back" ST-T wave configuration, in which the elevated ST segment descends toward the baseline, then rises again to an upright or biphasic T wave (figure 1).
●The characteristic Brugada pattern ECG abnormalities may be exposed by a variety of medications and toxin, thereby identifying those at risk (table 3), as well as by fever. (See 'Provoking factors' above.)
●The diagnosis of Brugada syndrome is most commonly made following a clinically significant event (ie, syncope, sudden cardiac death) in which the patient has the typical Brugada pattern ECG findings. However, some patients may be diagnosed based on the presence of ECG findings and relevant family history of sudden cardiac death or Brugada ECG patterns. Because of the clinical variability in presentation and the different ECG manifestations which can be seen in the Brugada syndrome, diagnostic criteria have been proposed by professional societies from both Europe and North America. (See 'Diagnosis' above.)
●Once the diagnosis of Brugada syndrome is suspected based on the clinical presentation and ECG findings, additional evaluation may be required to confirm the diagnosis of Brugada syndrome and to provide an estimate of risk of ventricular arrhythmias and sudden cardiac death in the individual patient. Our approach to the evaluation and risk stratification of patients with Brugada pattern ECG finding depends in large part on the presence or absence of symptoms (see 'Evaluation and risk stratification' above):
•All patients with suspected Brugada syndrome, based on the combination of symptoms and typical Brugada pattern ECG changes (either type 1 or type 2), require an evaluation to exclude underlying structural heart disease (algorithm 1). This evaluation should include cardiac imaging (with echocardiography and, in selected cases, cardiac magnetic resonance imaging) and cardiac stress testing. Drug challenge may be necessary if the other evaluation has not confirmed the diagnosis.
•Patients with only a Brugada pattern ECG who are entirely asymptomatic do not meet the criteria for Brugada syndrome based on ECG findings alone. A comprehensive family history, cardiac imaging with echocardiography (and, in selected cases, cardiac magnetic resonance imaging) should be performed in these patients, with drug challenge, signal-averaged ECG, and invasive electrophysiology studies as potential additional tests of an asymptomatic patient with a Brugada pattern ECG.
●We suggest genetic testing for all patients with documented Brugada syndrome ("probands"). If the proband has an identified genetic mutation (ie, genotype positive), we pursue genetic testing in all of the proband's first degree relatives. We do not recommend genetic testing for Brugada pattern ECG probands or their first degree relatives. (See 'Genetic testing' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Ann Garlitski, MD, who contributed to earlier versions of this topic review.
