A pharmacologic challenge with one of the class I antiarrhythmic agents (Table 1), which block INa, may be used as a diagnostic tool for susceptible patients by unmasking the type 1 pattern5,11,16. The 2016 expert consensus on J-wave syndromes5 expresses concerns about the potential for overdiagnosis of BrS, particularly in patients displaying a type 1 pattern only after a drug challenge, contrasting with the previous 2013 consensus statement on inherited cardiac arrhythmias6. Thus, it is now suggested that development of a type 1 pattern with this test should be considered as probabilistic rather than binary in nature. The same may apply to the interpretation of a genetic test5.

The 2016 consensus report5 recommends that only a type 1 (coved-type) ST-segment elevation is considered diagnostic of BrS (Figure 1), specifically an elevation of ≥2mm (0.2mV) in ≥1 right precordial leads (V1–V3) positioned in the 4th, 3rd, or 2nd intercostal space. Type 2 (saddleback-type) is characterized by ST-segment elevation of ≥0.5mm (generally ≥2mm in V2) in ≥1 right precordial lead (V1-V3), followed by a convex ST, and by a positive T wave in V2 and variable morphology in V1. Type 3 pattern is characterized by either a saddleback or coved appearance with an ST-segment elevation of <1mm. Type 2 or type 3 ST-segment elevation can be used for the diagnosis of BrS only if converted to type 1 with fever or pharmacologic challenge. However, when a type 1 ECG is unmasked using drug challenge, diagnosis of BrS should require that the patient also present with at least one of the following: documented VF or PVT, syncope of probable arrhythmic cause, a family history of SCD at <45 years old with negative autopsy, coved-type ECGs in family members, or nocturnal agonal respiration. A pharmacologic challenge may therefore be useful only when there is clinical suspicion of BrS in the absence of spontaneous type 1 ST-segment elevation. Alternatively, programmed ventricular stimulation inducing VT/VF with one or two premature beats may also support the diagnosis when the above clinical features are present5.

Figure 1.

Type 1 (coved-type) Brugada syndrome electrocardiogram present in V1 and V2 (courtesy of Prof. P.G. Postema and ECGpedia.org).

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It is recommended that electrocardiographic recordings be obtained in the standard and superior positions for the V1 and V2 leads, because placement in more cranial positions (in the 3rd or 2nd intercostal space) increases the sensitivity of the ECG5. An alternative diagnostic tool, the full stomach test, in which ECGs are performed before and after a large meal, has been proposed for diagnosing BrS21. It is reasonable to assume that a spontaneous type 1 recorded by Holter at night or after a large meal has more diagnostic and prognostic value than a drug-induced type 15.

The criteria of the Proposed Shanghai BrS Score for the diagnosis of BrS are based on the ECG, clinical history, family history and genetic test results, but this score needs to be validated in further studies5.

Other circumstances can produce a type 1 Brugada-like ECG (ST-segment elevation mimicking a type 1 Brugada pattern) (Table 2)5,7,8. These are separate clinical entities with different pathophysiologies and prognosis and can thus be interpreted as confounding factors; they should be excluded before the establishment of a definitive diagnosis of BrS3,5,8.

The pathophysiology of BrS is only partially understood8. There are two main theories, the repolarization hypothesis and the depolarization hypothesis5,22,23.

The repolarization theory suggests that a decrease in inward currents (INa and ICa) and/or increase in outward currents (Ito) results in an outward shift in the balance of the ionic currents active at the end of phase 1 of the action potential (AP) in the right ventricular (RV) epicardium, where Ito is prominent. This results in loss of the AP dome and accentuation of the AP notch in the epicardium but not the endocardium, creating a transmural voltage gradient manifested by the characteristic Brugada ST-segment elevation on the ECG and dispersion of repolarization within the epicardium and transmurally. These repolarization abnormalities can precipitate the development of phase 2 reentry (local re-excitation), which in turn generates closely coupled premature beats as ventricular extrasystoles capable of precipitating PVT/VF23,24.

According to the depolarization theory, conduction slowing and delay, particularly in the right ventricular outflow tract (RVOT), results in delayed and abnormal depolarization currents that may play a primary role in the pathophysiology and arrhythmic manifestations of the syndrome22,23. Mild structural changes, such as increased collagen and fibrosis, and reduced expression of the gap junction protein connexin-43 especially (but not exclusively) in the RVOT, are a part of BrS and could account for the conduction abnormalities and also late potentials4. Further evidence supporting delayed depolarization includes the observation of late potentials and low-voltage fragmented electrogram activity in the RVOT and the RV anterior wall, and the beneficial effect of radiofrequency ablation on these epicardial sites of slow conduction in BrS patients4,25.

Despite the controversy, these two theories are not necessarily mutually exclusive and may indeed be synergistic5,26.

Certain agents and conditions (Table 3) may act as modulating factors by influencing and interfering with cardiac ion channel function, unmasking the characteristic Brugada ECG pattern and possibly leading to fatal consequences, particularly in BrS patients, because of already impaired cardiac ion channel function3,5,16,17.

BrPs are clinical entities that have visually similar or even identical ECG patterns to true congenital BrS but are etiologically distinct, being elicited by a variety of other clinical circumstances57,72,73. The term phenocopy describes a phenotype which is caused by environmental conditions that matches one determined by a gene, and so the absence of any apparent genetic abnormality is central to the concept of BrP; the environmental factors alone are sufficient to result in a BrS pattern rather than unmasking latent BrS57,73–75. These factors may include myocardial ischemia, hyponatremia, hyperkalemia (Figure 2), hypokalemia, hypophosphatemia (Figure 3), pulmonary embolism, concomitant alcohol and heroin overdose, hypothermia, hypopituitarism, mechanical mediastinal compression, electrocution (Figure 4), and poor ECG filters; they are categorized by etiology in Table 638,73–87. The website www.brugadaphenocopy.com was recently created to establish an online international database of BrP cases to allow for longitudinal follow-up of these conditions and to develop a better understanding of BrP74. Notably, a recent report of recurrent hypokalemia demonstrated clinically reproducible BrP, contributing to the evolution of the concept79.

Figure 2.

Type 1 Brugada phenocopy electrocardiogram in V1-V2 and type 2 Brugada phenocopy electrocardiogram in V3, in the context of hyperkalemia. Retrieved from Dendramis et al.78.

(0.45MB).

Figure 3.

Type 1 Brugada phenocopy electrocardiogram in V1-V3, in the context of hypophosphatemia. Retrieved from Meloche et al.80.

(0.2MB).

Figure 4.

Type 1 Brugada phenocopy electrocardiogram in V1 and type 2 Brugada phenocopy ECG in V2, in the context of electrocution. Retrieved from Wang et al.85.

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In order to differentiate BrP from true congenital BrS, the criteria summarized in Table 7 can be used to assist with recognition and diagnosis of BrP. Unlike in BrS, in BrP there is usually an identifiable and reversible underlying condition, resolution of which is accompanied by prompt normalization of the ECG. Additionally, these patients have low clinical probability for BrS, as indicated by the absence of a documented personal history of SCA or syncope, or family history of SCD. Finally, drug challenge testing is negative, while in BrS patients this tends to be positive73,74. The differences in ECG response to drug challenge denote pathophysiological differences between BrP and BrS, suggesting alternative underlying mechanisms with various genetic, structural and environmental interactions that are yet to be elucidated73. While high-risk patients with BrS may be candidates for an implantable cardioverter-defibrillator (ICD), the clinical implications of BrP, and hence the correlation between BrP and malignant VA, remain unknown5,57,73. At this time, the recommended approach for BrP is mainly based on systematic diagnostic procedures (to differentiate BrP from BrS) and resolution of the underlying condition73,74.

The congenital BrS ECG pattern is often dynamic and concealed, but it can be unmasked, modulated or precipitated by a wide range of agents and conditions, which are summarized in Table 33,5,8. Associated malignant VAs can develop under most of these circumstances in BrS patients, because these individuals already have impaired cardiac ion channel function3,5,17. This association with VA and SCD is more evident with fever15,32–36, with certain drugs that are indicated to be avoided by BrS patients (Table 4)16 and energy drinks56, under vagotonic conditions9,12,13 such as a large meal21,58,59 or the recovery phase of exercise14,60,61, with hypertestosteronemia62,63 or hyperthyroidism64, and possibly with potassium imbalance65–68. Fever is recognized as a major risk factor in BrS and can even outperform drug challenge in unmasking a type 1 ECG5,28,32. Junttila et al.36 reported that patients presenting with a Brugada ECG during an acute event, including fever, treatment with medication affecting INa, drug overdose or electrolyte imbalances, should be considered to have a higher risk of life-threatening VA and SCD, even in the absence of an SCN5A mutation. It is also plausible that the cardiac electrophysiological mechanisms involved in acidosis and ischemic heart disease may potentiate those of BrS, resulting in increased risk for VA in BrS patients52,67,88. In most of such cases, the type 1 pattern and associated VAs presumably result from induced or exacerbated decrease in inward currents (INa and ICa) or increase in outward currents (Ito or IK-ATP)3,5,20. There is now a growing consensus that apart from genetic factors, the expression of BrS is also multifactorial, the underlying genetic predisposition being modulated by diverse environmental factors and even morphologic cardiac changes4,5.

Equally important, there are also cases of acquired forms of BrS in which, theoretically, an intervention (such as administration of a pharmacologic agent) could have caused a sufficient imbalance of inward and outward currents in the RVOT to induce a Brugada pattern17–20,75. These patients are typically asymptomatic, without a personal or family history of VA, and may test positive on drug challenge. It is not yet established whether this requires an underlying genetic predisposition or actually represents latent BrS18,75. However, the susceptibility of these individuals may be due to genetic polymorphisms rather than pathogenic mutations17,75,89. Such a genetic predisposition or subclinical form (forme fruste) may result in increased latent ion channel dysfunction that favors induction of a Brugada pattern, particularly when there is a specific combination of stressors and comorbidities, similar to what is observed with acquired long QT syndrome (LQTS)17,18,75,90. However, the likelihood of arrhythmias is still unclear18,75.

In principle, a risk profile for a D-type 1 pattern and VA could be drawn up based on various factors such as male gender, genetic predisposition and modulating polymorphisms, specific electrolyte disturbances, fever, kidney and liver dysfunction, cardiac comorbidities, the use or excessive doses of specific drugs, electrocardiographic characteristics, and previous arrhythmias17,91. Konigstein et al.92 recently documented that the D-type 1 ECG associated with non-cardiac drugs is seen mostly in adult males, is frequently due to drug toxicity, and develops late after the onset of therapy. However, it would be difficult to apply these data to a specific individual, because of the wide variability in response to a specific drug, and because its possible effects may change over time depending on treatment duration, age, or developing comorbidities. Furthermore, most of the evidence supporting the association with VAs comes from a limited number of case reports, laboratory studies and cohort analyses16,17. It would therefore be difficult to predict the likelihood of drug-induced BrS in routine clinical practice17,19,91.

Clinical presentation is still the strongest predictor of risk in BrS, and in asymptomatic patients the arrhythmic risk is low (0.5% per year). Furthermore, asymptomatic patients with a type 1 pattern that only develops following drug challenge have a lower risk of arrhythmic events during follow-up than those with a spontaneous type 1 at diagnosis5,93. Unlike high-risk BrS patients, who may have indication for an ICD, asymptomatic patients with a type 1 pattern only disclosed by drug challenge may be indicated for close follow-up only5,6. The prognosis of asymptomatic patients with a D-type 1 pattern but without a family history of SCD appears to be relatively benign once the offending agent is discontinued5,18. Nevertheless, it may be prudent not to ignore the risk, particularly during exposure to the agent16–19,36,41,91.

There is considerable debate concerning the appropriate terminology for BrP, mainly because it is very difficult to rule out a genetic predisposition. Antzelevitch et al. have accordingly proposed that these conditions be designated acquired forms of Brugada ECG pattern or BrS, as more in line with the terminology used in LQTS.5 At this stage, there is a need to clarify the concepts and real significance of acquired Brugada patterns and BrP as clinical entities, especially in terms of arrhythmic risks and prognosis, and to gain a better understanding of their underlying mechanisms and the possible genetic predisposition in the case of acquired BrS. Thus, more systematic, population-based, observational and experimental studies are needed to clarify these concepts and to better differentiate them from each other and from BrS itself.

Nevertheless, in a patient with an induced type 1 Brugada pattern, it seems prudent to proceed with a systematic diagnostic approach, excluding confounding factors (Table 2), identifying possible underlying modulators (Table 3), investigating whether the ECG normalizes on resolution of possible environmental factors, investigating personal and family history of symptoms and arrhythmias (including SCD), performing a drug challenge (Table 1), and possibly undertaking genetic study, including of the patient's family5,8,19,73. Additionally, distinguishing true BrS from BrP is crucial, because the type 1 pattern in BrS can be transient and indistinguishable from BrP and possibly provoked by the same conditions, such as hyperkalemia66,72–74,78. Moreover, the propensity for VA in BrS is established, whereas this is not the case for BrP73,74. Since the prognosis of BrP may be related to the evolution of the underlying condition73,74, and a type 1 Brugada ECG may itself be an indicator of increased risk for arrhythmias17, it makes sense to screen for and promptly correct any underlying conditions or possible modulating factors5,73,74. Fever in BrS patients should be treated aggressively with antipyretics, and they should avoid the substances listed in Tables 4 and 5 and be familiar with the effects of a large meal, especially after a long fasting period5,16–19,59. Data on the risks of exercise in BrS are currently too limited to make recommendations concerning exercise5,60. However, it is suggested that BrS patients should avoid vigorous exercise60,61.