J Wave Syndromes Consensus Conference: Emerging Concepts & Gaps in Knowledge

Preamble

The J wave syndromes, consisting of the Brugada (BrS) and Early Repolarization Syndromes (ERS), have captured the interest of the cardiology community over the past two decades, following the identification of BrS as a new clinical entity by Pedro and Josep Brugada in 1992.¹ The clinical impact of ERS was not fully appreciated until 2008.^2,3,4 Consensus conferences dedicated to BrS were held in 2000 and 2004.^{5, 6} A consensus conference specifically focused on ERS has not previously been convened other than that dealing with terminology, and Guidelines for both syndromes were last considered in 2013.⁷ A great deal of new information has emerged since. The present forum was organized to evaluate new information and highlight emerging concepts with respect to differential diagnosis, prognosis, cellular and ionic mechanisms, and approaches to therapy of the J wave syndromes. Leading experts, including members of the Heart Rhythm Society (HRS), the European Heart Rhythm Association (EHRA) and the Asian-Pacific Heart Rhythm Society (APHRS) met in Shanghai, China, in April 2015. The task force was charged with a review of emerging concepts and assessment of new evidence for or against particular diagnostic procedures and treatments. Every effort was made to avoid any actual, potential, or perceived conflict of interest that might arise as a result of outside relationships or personal interest. This consensus report is intended to assist healthcare providers in clinical decision making. The ultimate judgment regarding care of a particular patient, however, must be made by the healthcare provider based on all of the facts and circumstances presented by the patient.

Members of this Task Force were selected to represent professionals involved with the medical care of patients with the J wave syndromes, as well as those involved in research into the mechanisms underlying these syndromes. These selected experts in the field undertook a comprehensive review of the literature. Critical evaluation of methods of diagnosis, risk stratification, approaches to therapy and mechanistic insights was performed, including assessment of the risk–benefit ratio. The level of evidence and the strength of the recommendation of particular management options were weighed and graded. Recommendations with Class designations are taken from HRS, EHRA, APHRS, and/or ESC consensus statements or guidelines.^{8, 9} Recommendations without Class designations are derived from unanimous consensus of the authors. The consensus recommendations in this document use the commonly used Class I, IIa, IIb and III classifications and the corresponding language: “is recommended” for Class I consensus recommendation; “can be useful” or “is reasonable” for a Class IIa; “may be considered” to signify a Class IIb; and “is not recommended” for a Class III consensus recommendation.

Introduction

The appearance of prominent J waves in the electrocardiogram (ECG) have long been reported in cases of hypothermia^10-12 and hypercalcemia.^{13, 14} More recently, accentuation of the J wave has been associated with life-threatening ventricular arrhythmias.¹⁵ Under these circumstances, the accentuated J wave typically may be so broad and tall as to appear as an ST segment elevation, as in cases of Brugada syndrome (BrS). In humans, the normal J wave often appears as a J point elevation, with part of the J wave buried inside the QRS. An early repolarization (ER) pattern in the ECG, consisting of a distinct J wave or J point elevation, a notch or slur of the terminal part of the QRS with and without an ST segment elevation, has traditionally been viewed as benign.^{16, 17} The benign nature of an ER pattern was challenged in 2000¹⁸ on the basis of experimental data showing that this ECG manifestation predisposes to the development of polymorphic ventricular tachycardia and fibrillation (VT/VF) in coronary-perfused wedge preparations.^{15, 18-20} Validation of this hypothesis was provided eight years later by Haïssaguerre et al.,² Nam et al.³ and Rosso et al.⁴ These seminal studies together with numerous additional case control and population-based studies have provided clinical evidence for an increased risk for development of life-threatening arrhythmic events and sudden cardiac death (SCD) among patients presenting with an ER pattern, particularly in inferior and infero-lateral leads. The lack of agreement regarding the terminology relative to ER has led to a great deal of confusion and inconsistency in reporting.^21-23 A recent expert consensus report focused on the terminology of early repolarization recommends that peak of an end QRS notch and/or the onset of an end QRS slur be designated as J_p and that J_p should exceed 0.1mV in ≥2 contiguous inferior and/or lateral leads of a standard 12-lead ECG for early repolarization to be present.²⁴ It was further recommended that the start of the end QRS notch or J wave be designated as J_o and the termination as J_t.

Early repolarization syndrome (ERS) and BrS are thought to represent two manifestations of the J wave syndromes. Both syndromes are associated with vulnerability to development of polymorphic ventricular tachycardia (VT) and ventricular fibrillation (VF) leading to SCD^{1-3, 15} in young adults with no apparent structural heart disease and occasionally to sudden infant death syndrome.^25-27 The region generally most affected in BrS is the anterior right ventricular outflow tract; in ERS, it is the inferior region of the left ventricle.^{2, 4, 28-32} As a consequence, BrS is characterized by accentuated J waves appearing as a coved-type ST segment elevation in the right precordial leads V1-V3, whereas ERS is characterized by J waves, J_o elevation, notch or slur of the terminal part of the QRS and ST-segment or J_t elevation in the lateral (type I), infero-lateral (type II) or in infero-lateral + anterior or right ventricular leads (type III).¹⁵ Early repolarization pattern (ERP) is often encountered in ostensibly healthy individuals, particularly in young males, black individuals and athletes. ERP is also observed in acquired conditions, including hypothermia and ischemia.^{15, 33, 34} When associated with VT/VF in the absence of organic heart disease, ERP is referred to as early repolarization syndrome (ERS).

The prevalence of BrS with a type 1 ECG in adults is higher in Asian countries, such as Japan (0.15 to 0.27%),^{35, 36} the Philippines (0.18%),³⁷ and among Japanese-Americans in North America (0.15%)³⁸ than in Western countries, including Europe (0 to 0.017%)^39-41 or North America (0.005 to 0.1%).^{42, 43} In contrast, the prevalence of an ER pattern in the inferior and/or lateral leads with a J point elevation of ≥ 0.1mV ranges between 1% and 24%, and for J point elevation of > 0.2 mV, it ranges between 0.6% to 6.4%.^44-46 No significant regional differences have been reported in the prevalence of an ER pattern.⁴⁷ However, ER pattern is significantly more common in blacks than in Caucasians. Little in the way of regional differences in the manifestation of ERS has been reported. Early repolarization pattern appears to be more common in Aboriginal Australians than in Caucasian Australians.⁴⁸

Updates on the Diagnosis of BrS

According to the 2013 Consensus statement on inherited cardiac arrhythmias⁸ and 2015 Guidelines for the management of patients with ventricular arrhythmias and prevention of sudden cardiac death⁹: “BrS is diagnosed in patients with ST-segment elevation with type 1 morphology ≥2 mm in ≥1 lead among the right precordial leads V1, V2, positioned in the 2nd, 3^rd or 4^th intercostal space occurring either spontaneously or after provocative drug test with intravenous administration of Class I antiarrhythmic drugs. BrS is diagnosed in patients with type 2 or type 3 ST-segment elevation in ≥1 lead among the right precordial leads V1, V2 positioned in the 2nd, 3^rd or 4^th intercostal space when a provocative drug test with intravenous administration of Class I antiarrhythmic drugs induces a type I ECG morphology.”

The present task force is concerned that this could result in an over-diagnosis of BrS, particularly in patients displaying a Type 1 ECG only after a drug challenge. Data suggest the latter population is at very low risk, and that the presumed false positive rate of pharmacologic challenge is not trivial ⁴⁹. Though a rigorous process was undertaken to establish the preceding guidelines, there remains no gold standard for establishing a diagnosis, particularly in patients with weak evidence of disease. Accordingly, we recommend adoption of the following diagnostic criteria and score system for BrS. Consistent with the recommendation of the 2013 and 2015 guidelines, only a Type 1 (“coved type”) ST segment elevation is considered diagnostic of BrS (Figure 1), and BrS is characterized by ST segment elevation ≥2 mm (0.2 mV) in ≥1 right precordial leads (V1-V3) positioned in the 4^th, 3^rd or 2^nd intercostal space. However, as a departure from the guidelines, this consensus report recommends that when a Type 1 ST segment elevation is unmasked using sodium channel blockers (Table 1), diagnosis of BrS should require that the patient also present with one of the following: documented VF or polymorphic ventricular tachycardia, syncope of probable arrhythmic cause, a family history of sudden cardiac death at <45 years old with negative autopsy, coved-type ECGs in family members, or nocturnal agonal respiration. Inducibility of VT/VF with one or two premature supports the diagnosis of BrS under these circumstances.⁵⁰

Figure 1.

Three types of ST segment elevation associated with Brugada syndrome. Only Type 1 is diagnostic of BrS.

Table 1.

Drugs used to unmask the Brugada electrocardiogram.

Drug	Dose	Administration
Ajmaline	1 mg/kg over 10 minutes	Intravenous
Flecainide	2 mg/kg over 10 minutes 200-300 mg	Intravenous Oral (>1 hour)
Procainamide	10 mg/kg over 10 minutes	Intravenous
Pilsicainide	1 mg/kg over 10 minutes	Intravenous

A Type 2 (“saddle-back type”) or Type 3 ST segment elevation cannot substitute for a Type 1, unless converted to Type 1 with fever or sodium drug challenge. A drug-challenge-induced Type 1 can be used to diagnose BrS only if accompanied by one of the criteria specified above. Type 2 is characterized by ST segment elevation of ≥0.5 mm (generally ≥2 mm in V2) in ≥1 right precordial lead (V1-V3), followed by a convex ST. The ST segment is followed by a positive T wave in V2 and variable morphology V1. Type 3 is characterized by either a saddleback or coved appearance with an ST-segment elevation of <1 mm. The placement of the right precordial leads in more cranial positions (in the 3^rd or 2^nd intercostal space) in a 12-lead resting ECG or 12-lead Holter ECG increases the sensitivity of ECG.^51-53 It is recommended that ECG recordings be obtained in standard and superior positions for the V1 and V2 leads. Veltman et al. showed that RV outflow tract (RVOT) localization using MRI correlates with Type 1 ST segment elevation in BrS and that lead positioning according to RVOT location improves the diagnosis of BrS. Interestingly, a Type I pattern was in most cases found in the 3rd intercostal space in sternal and left-parasternal positions.⁵⁴ In reviewing ECGs of a large cohort of BrS patients, Richter et al. concluded that lead V3 does not yield diagnostic information in BrS.⁵⁵

A proposed Diagnostic Score System for BrS, referred to as the Proposed Shanghai BrS Score, is presented in Table 2. These recommendations are based on the available literature and on the clinical experience of members of the task force.^{8, 56-60} Weighting of variables is based on expert opinion informed by cohort studies that typically do not include all variables presented. Thus, rigorous, objectively weighted coefficients were not derived from large-scale risk factor and outcome-informed datasets. Nonetheless, the authors felt that some inferential weighting would be of benefit when applied to patients. As with all such recommendations they will need to undergo initial and ongoing validation by future studies.

Table 2.

Proposed Shanghai Score System for Diagnosis of Brugada Syndrome

I. ECG (12-Lead/Ambulatory)	Points
A. Spontaneous Type 1 Brugada ECG pattern at nominal or high leads	3.5
B. Fever-induced Type 1 Brugada ECG pattern at nominal or high leads		3
C. Type 2 or 3 Brugada ECG pattern that converts w/ provocative drug challenge	2
*Only award points once for highest score within this category. One item from this category must apply.
II. Clinical History*
A. Unexplained cardiac arrest or documented VF/polymorphic VT	3
B. Nocturnal agonal respirations	2
C. Suspected arrhythmic syncope	2
D. Syncope of unclear mechanism/unclear etiology	1
E. Atrial flutter/fibrillation in patients < 30 years without alternative etiology	0.5
*Only award points once for highest score within this category.
III. Family History
A. 1st or 2nd degree relative with definite BrS	2
B. Suspicious SCD (fever, nocturnal, Brugada aggravating drugs) in a 1st or 2nd degree relative	1
C. Unexplained SCD < 45 years in first/second degree relative with negative autopsy	0.5
*Only award points once for highest score within this category.
IV. Genetic Test Result
A. Probable pathogenic mutation in BrS-susceptibility gene	0.5
SCORE (Requires at least 1 ECG finding)
> 3.5 points – Probable/Definite BrS
2 – 3 points – Possible BrS
< 2 points – Non-Diagnostic

Pharmacological tests and other diagnostic tools

When there is clinical suspicion of BrS in the absence of spontaneous Type 1 ST segment elevation, a pharmacological challenge using a sodium channel blocker is recommended. A list of agents used for this purpose is presented in Table 1 (also see www.brugadadrugs.org). The test is considered positive only if a Type 1 ECG pattern is obtained, and it should be discontinued in case of frequent ventricular extrasystoles or other arrhythmias, or widening of the QRS >130% over the baseline value.⁶ As an alternative, the “full stomach test” has been proposed for diagnosing BrS.⁶¹ In this case, ECGs are performed before and after a large meal. The use of “high-electrodes” increases the sensitivity for recognizing spontaneous Type I ST segment elevation at night or after heavy meals.⁶² A Type 1 ST segment elevation recorded using a Holter is a spontaneous Type 1, and it is reasonable to assume that a spontaneous Type 1 recorded by Holter at night or after a large meal has more value — both diagnostic and prognostic — than a drug-induced Type 1.

Drug challenge is not indicated in asymptomatic patients displaying the Type 1 ECG under baseline conditions because of the lack of the additional diagnostic value. These provocative drug tests are also not recommended in cases in which fever has been documented to induce a Type I ECG, other than for research purposes. Much debate has centered around the definition of a false positive sodium channel block challenge.⁶³ The consensus is that it is difficult to define a false positive because of the lack of a gold standard. The development of a Type 1 ST segment elevation in response to sodium block challenge should be considered as probabilistic, rather than binary, in nature. As will be discussed below, a similar approach is recommended in evaluating the ability of genetic variants to promote the BrS phenotype.

Asymptomatic patients with a family history of BrS or SCD should be informed of the availability of a sodium channel blocker challenge test to provide a more definitive diagnosis of BrS. However, patients should be advised that no therapy may be recommended regardless of the outcome, because the long-term risk of patients with BrS diagnosed by this test is significantly lower than the risk of patients with spontaneous Type 1. Patients should also be informed about the risk of the test and about the emotional consequences of having a positive test not followed by definitive therapy. The decision as to whether to undergo the drug challenge ultimately should be left up to the well-informed patient.

Performing an ajmaline test in children is problematic for two reasons: First, the test is apparently less sensitive in children than in adults. In fact, in one study, a repeat ajmaline challenge performed after puberty unmasked BrS in 23% of relatives with a previously negative drug test performed during childhood.⁶⁴ Second, the test is associated with greater risk than in adults. In one series, 10% of children undergoing the ajmaline test, including 3% of the asymptomatic subgroup, developed sustained VT.^{64, 65} Caution should also be exercised when performing a sodium blocker challenge in adults with a known pathogenic sodium channel mutation or in patients with prolonged PR intervals, pointing to a carrier of such a mutation. ⁶⁶

Differential diagnosis

Other causes of ST segment elevation should be excluded before establishing the diagnosis of BrS (Table 3). Artifacts secondary to low-pass filtering should be ruled out.⁶⁷

Table 3.

Differential diagnosis and modulating factors in Brugada Syndrome.

A. Differential diagnosis

B. Modulating factors

Atypical right bundle branch block Ventricular hypertrophy Early repolarization (especially in athletes) Acute pericarditis/myocarditis Acute myocardial ischemia or infarction (especially of the right ventricle) Pulmonary thromboembolism Prinzmetal angina Dissecting aortic aneurism Central and autonomic nervous systems abnormalities Duchenne’s muscular dystrophy Friedreich’s ataxia Spinobulbar Muscular Atrophy Myotonic Dystrophy Arrhythmogenic right ventricular dysplasia Mechanical compression of the right ventricular outflow tract (e.g., pectus excavatum, mediastinal tumor, hemopericardium, Hypothermia Post-defibrillation ECG

Electrolyte abnormalities: ○ Hyperkalemia ○ Hypokalemia ○ Hypercalcemia ○ Hyponatremia Temperature: hyperthermia (fever), hypothermia Hypertestosteronemia Treatment with: ○ Antiarrhythmic drugs: sodium channel blockers (class IC, class IA), calcium antagonists, beta-blockers ○ Antianginal drugs: calcium antagonists, nitrates, potassium channel openers ○ Psychotropic drugs: tricyclic/tetracyclic antidepressants, phenothiazines, selective serotonin reuptake inhibitor, lithium, benzodiazepines ○ Anesthetics/analgesics: propofol, bupivacaine, procaine ○ Others: histamine H1 antagonist, alcohol intoxication, cocaine, cannabis, ergonovine

Circumstances that produce a Type 1 Brugada-like ECG include right bundle branch block (RBBB), pectus excavatum, arrhythmogenic right ventricular cardiomyopathy (ARVC), as well as occlusion of the left anterior descendent artery or the conus branch of the right coronary artery, which supplies the RVOT (Table 3A).

Discrimination between BrS and ARVC is particularly challenging. Although debate continues as to the extent to which structural abnormalities are present in BrS, most investigators consider BrS to be a channelopathy. Concealed structural abnormalities, such as histologic myocardial fibrosis of the RVOT, which may not become evident using conventional imaging techniques, have been proposed to account for or contribute to delayed conduction and ventricular arrhythmias in BrS. MRI and electron beam computed tomography studies of BrS patients consistently show subtle abnormalities, including wall motion abnormalities and reduced contractile function of the right ventricle (RV) and to a lesser extent of the left ventricle (LV), and dilatation of the RVOT.^68-71 In the only study that discriminated between patients with and without SCN5A mutations, no difference was observed in RVOT dimensions or RV ejection fraction between such patients. Slightly greater depression of LV dimensions and ejection fraction were observed in patients with SCN5A mutations. Significant differences were observed in RV and LV dimensions and ejection fraction when compared to healthy controls.⁷² Cardiac dilatation and reduced contractility in all of these studies were attributed to structural changes (fibrosis, fatty degeneration). However, as noted by van Hoorn and co-workers, virtually no signs of fibrosis or fatty degeneration could be detected, perhaps due to the fact that the spatial resolution of imaging used was too low to detect such subtle changes.⁷²

Antzelevitch and colleagues have long suggested an alternative explanation.^{31, 73, 74} Loss of the action potential (AP), which has been shown in experimental models to create the arrhythmogenic substrate in BrS, leads to contractile changes that could explain the wall motion abnormalities observed. The all-or-none repolarization at the end of phase 1 of the epicardial AP responsible for loss of the dome causes the calcium channel to inactivate very soon after it activates. As a consequence, calcium channel current is dramatically reduced, the cell becomes depleted of calcium, and contractile function ceases in those cells. This is expected to lead to wall motion abnormalities, particularly in the RVOT, dilatation of the RVOT region and reduced ejection fraction observed in patients with BrS. It has also been proposed that the loss of the AP dome, because it creates a hibernation-like state, may, over long periods of time, lead to mild structural changes, including intracellular lipid accumulation, vacuolization and connexin 43 redistribution. These structural changes may, in turn, contribute to the arrhythmogenic substrate of BrS, although they are very different from those encountered in ARVC/D.^{31, 75} This hypothesis would predict that some of the changes observed by recent studies⁷⁶ may be the result of, rather than the cause of, the BrS phenotype.

A recent study by Nademanee et al. reports additional evidence pointing to pathological changes in the RVOT of patients with BrS that have proved undetectable by echocardiography or MRI.⁷⁶

In contrast, imaging techniques in ARVC clearly display morphological and functional changes (e.g., dilatation, bulging/aneurysms, wall motion abnormalities). ARVC is an inherited cardiac disease resulting from genetically defective desmosomal (DS) proteins,^{77, 78} characterized by fibro-fatty myocardial replacement predisposing to scar-related ventricular arrhythmias that may lead to SCD, mostly in young people and athletes.⁷⁹ Life-threatening ventricular arrhythmias may occur early, during the “concealed phase” of the disease, prior to overt structural changes.^{77, 78, 80} Recent experimental studies demonstrated that loss of expression of DS proteins may induce electrical ventricular instability by causing sodium channel dysfunction and current reduction as a consequence of the cross-talk between these molecules at the intercalated discs, which predisposes to sodium current-dependent lethal arrhythmias, similarl to those leading to SCD in patients with J-wave/Brugada syndromes.^80-82 Further evidence of the overlap between phenotypic manifestation of ARVC and J-wave/Brugada syndromes comes from: 1) clinic-pathologic studies showing that a subset of ARVC patients may share ECG changes and patterns of ventricular arrhythmias with BrS;⁸³ and 2) genotype-phenotype correlation studies demonstrating that PKP2 mutation may cause a Brugada phenotype in the human heart by reducing sodium current.⁸⁴ These findings support the concept that specific DS-gene mutations involved in the pathogenesis of ARVC can lead to a decreased depolarization reserve that manifests as J-wave/Brugada syndromes. Thus, ARVC and J-wave/Brugada syndromes are not completely different conditions, but the ends of a spectrum of structural myocardial abnormalities and sodium current deficiency that share a common origin as diseases of the connexome.⁸⁴ The ECG abnormalities in ARVC are not dynamic and display a constant T-wave inversion, epsilon waves and, in the progressive stage, reduction of the R amplitude. End-stage ARVC is usually associated with monomorphic VT with left bundle branch morphology and is precipitated by catecholamines,⁸⁵ whereas BrS is associated with polymorphic VT predominantly during sleep or rest.⁸⁶ A positive ajmaline challenge has been reported in 16% of patients with ARVC.^{87, 88}

Modulating factors

Sympatho-vagal balance, hormones, metabolic factors, and pharmacological agents are thought to modulate not only the ECG morphology but also explain the development of ventricular arrhythmias under certain conditions.⁸⁹ If any of these modulating factors is present, it should be promptly corrected (Table 3B).

Acquired Brugada pattern and phenocopies

The Brugada ECG is often concealed and can be unmasked with a wide variety of drugs and conditions, including a febrile state, vagotonic agents and maneuvers, α adrenergic agonists, β adrenergic blockers, Class IC antiarrhythmic drugs, tricyclic or tetracyclic antidepressants, hyperkalemia, hypokalemia, hypercalcemia, as well as by alcohol and cocaine toxicity.^90-100 Pre-excitation of RV can unmask the BrS phenotype in cases of RBBB.¹⁰¹ An up-to-date list of agents known to unmask the Brugada ECG and that should be avoided by patients with BrS can be found at www.brugadadrugs.org.⁸⁹

Environmental factors leading to the appearance of an ECG similar or identical to a Type 1 BrS pattern in the absence of any apparent genetic dysfunction has been suggested to represent a Brugada ECG phenocopy.¹⁰² Features of the Brugada phenocopies include: 1) Brugada-like ECG pattern; 2) presence of an identifiable underlying condition; 3) disappearance of the ECG pattern after resolution of the condition; 4) absence of family history of SD in relatively young first-degree relatives (≤45 years) or of Type 1 BrS pattern; 5) absence of symptoms such as syncope, seizures or nocturnal agonal respiration; and 6) a negative sodium channel-blocker challenge test. Debate continues as to the appropriateness of this terminology given that it is very difficult to rule out a genetic predisposition, which is a prerequisite for designating the ECG manifestation as a phenocopy. Designation of these conditions as acquired forms of Brugada ECG pattern or BrS may be more appropriate and better aligned with the terminology used in the long QT syndrome.

Update on the diagnosis of ERS

ERS is generally diagnosed in patients who display ER in the inferior and/or lateral leads presenting with aborted cardiac arrest, documented VF or polymorphic ventricular tachycardia. Consistent with the recent Consensus Report on ER pattern,²⁴ early repolarization is recognized if: 1) there is an end QRS notch (J wave) or slur on the downslope of a prominent R wave with and without an ST segment elevation; 2) the peak of the notch or J wave (Jp) ≥ 0.1mV in two or more contiguous leads of the 12 lead ECG, excluding leads V1-V3; and 3) QRS duration (measured in leads in which a notch or slur is absent) < 120ms. Table 4 lists the exclusion criteria in the differential diagnosis of ERS.

Table 4.

Differential diagnosis of ER Pattern

Other causes of ER pattern include:

Juvenile ST pattern Pericardial disease (pericarditis, pericardial cyst or pericardial tumor) Hypothermia Hyperthermia Myocardial tumor (Lipoma) Hypertensive heart disease Athlete’s heartMyocardial ischemia STEMI (i.e., anteroseptal MI) Fragmented QRS (terminal notching) Hypocalcemia Hyperpotassemia Thymoma Aortic Diseection ARVC Takotsub○ cardiomyopathy Neurological causes (intracerebral bleeding, acute brain injury) Myocarditis Chagas disease Cocaine use

A proposed Diagnostic Score System for ERS, referred to as the Proposed Shanghai ERS Score, is presented in Table 5. The scoring system is based on evidence available in the literature to date. As in BrS, weighting of variables is based on expert opinion informed by cohort studies that do not include all variables presented. Thus, rigorous, objectively weighted coefficients were not derived from large-scale risk factor- and outcome-informed datasets. Nonetheless, the authors felt that some inferential weighting would be of benefit when applied to patients. As with all such recommendations, they will need to undergo initial and ongoing validation by future studies.

Table 5.

Proposed Shanghai score system for diagnosis of Early Repolarization Syndrome

I. Clinical History
A. Unexplained cardiac arrest, documented VF or polymorphic VT	3
B. Suspected arrhythmic syncope	2
C. Syncope of unclear mechanism/unclear etiology	1
*Only award points once for highest score within this category
II. 12-Lead ECG
A. ER ≥ 0.2 mV in > 2 inferior and/or lateral ECG leads with horizontal/descending ST segment	2
B. Dynamic changes in J-point elevation (> 0.1 mV) in > 2 inferior and/or lateral ECG leads	1.5
C. ≥ 0.1 mV J-point elevation in at least 2 inferior and/or lateral ECG leads	1
*Only award points once for highest score within this category
III. Ambulatory ECG monitoring
A. Short coupled PVCs with R on ascending limb or peak of T wave	2
IV. Family History
A. Relative with definite ERS	2
B. > 2 first-degree relatives with a II.A. ECG pattern	2
C. A first-degree relative with a II.A. ECG pattern	1
D. Unexplained sudden cardiac death < 45 years in a first/second-degree relative	0.5
*Only award points once for highest score within this category
V. Genetic Test Result
A. Probable pathogenic ERS-susceptibility mutation	0.5
SCORE (Requires at least one ECG finding)
> 5 points – Probable/Definite ERS
3 – 4.5 points – Possible ERS
< 3 points – Non-Diagnostic

Similarities and difference between BrS and ERS

BrS and ERS display several clinical similarities, suggesting similar pathophysiology (Table 6).^{19, 21, 103-105} Males predominate in both syndromes: in BrS, presenting in 71%-80% among Caucasians and 94%-96% among Japanese.^{106, 107} In the setting of ER pattern, VF occurred mainly in males (72%) when studied in an international cohort,² but in a much higher percentage in a report by Japanese investigators.¹⁰⁸ BrS and ERS patients may be totally asymptomatic until presenting with cardiac arrest. In both syndromes, the highest incidence of VF or SCD occurs in the third decade of life, perhaps tied to testosterone levels in males.¹⁰⁹ In both syndromes, the appearance of accentuated J waves and ST segment elevation are generally associated with bradycardia or pauses.^{110, 111} This can explain why VF in both syndromes often occurs during sleep or at a low level of physical activities.^{108, 112} The QT interval is relatively short in patients with ERS^{2, 113} and BrS who carry mutations in calcium channel genes.¹¹⁴

Table 6.

Similarities and differences between Brugada and Early Repolarization Syndromes and possible underlying mechanisms

	BrS	ERS	Possible Mechanism(s)
Similarities between BrS and ERS
Male Predominance	Yes (>75%)	Yes (>80%)	Testosterone modulation of ion currents underlying the epicardial AP notch
Average age of first event	30-50	30-50
Associated with mutations or rare variants in KCNJ8, CACNA1C, CACNB2, CACNA2D, SCN5A, ABCC9, SCN10A	Yes	Yes	Gain of function in outward currents (IK- ATP) or loss of function in inward currents (ICa or INa)
Relatively short QT intervals in subjects with Ca channel mutations	Yes	Yes	Loss of function of ICa
Dynamicity of ECG	High	High	Autonomic modulation of ion channel currents underlying early phases of the epicardial AP
VF often occurs during sleep or at a low level of physical activity	Yes	Yes	Higher level of vagal tone and higher levels of Ito at the slower heart rates
VT/VF trigger	Short- coupled PVC	Short- coupled PVC	Phase 2 reentry
Ameliorative response to quinidine and bepridil	Yes	Yes	Inhibition of Ito and possible vagolytic effect
Ameliorative response to isoproterenol denopamine and milrinone	Yes	Yes	Increased ICa and faster heart rate
Ameliorative response to cilostazol	Yes	Yes	Increased ICa, reduced Ito and faster heart rate
Ameliorative response to pacing	Yes	Yes	Reduced availability of Ito due to slow recovery from inactivation
Vagally mediated accentuation of ECG pattern	Yes	Yes	Direct effect to inhibit ICa and indirect effect to increase Ito (due to slowing of heart rate)
Effect of sodium channel blockers on unipolar epicardial electrogram	Augmented J waves	Augmented J wave	Outward shift of balance of current in the early phases of the epicardial action potential
Fever	Augmented J waves	Augmented J waves (rare)	Accelerated inactivation of INa and accelerated recovery of Ito from inactivation.
Hypothermia	Augmented J waves mimicking BrS	Augmented J waves	Slowed activation of ICa, leaving Ito unopposed. Increased phase 2 reentry, but reduced pVT due to prolongation of APDR358
Differences between BrS and ERS
Region most involved	RVOT	Inferior LV wall	Higher levels of Ito and/or differences in conduction
Leads affected	V1-V3	II, II a, VF, V4, V5, V6; I, aVL, Both: infero-lateral
Regional difference in prevalence			Europe: BrS = ERS Asia: BrS > ERS
Incidence of late potential in SAECG	Higher	Lower
Prevalence of atrial fibrillation	Higher	Lower
Effect of sodium channel blockers on the surface ECG	Increased J wave manifestation	Reduced J wave Manifestation	Reduction of J wave in the setting of ER is thought to be due largely to prolongation of QRS. Accentuation of repolarization defects predominates in BrS, whereas accentuation of depolarization defects predominates in ERS.
Structural changes–including mild fibrosis and reduced expression of Cx43 in RVOT or fibro-fatty infiltration in cases of ARVC. Imaging studies have also revealed wall motion abnormalities and mild dilatation in the region of the RVOT.	Higher in some forms of the syndrome	Unknown	Some investigators have hypothesized that some of these changes may be the result of, rather than the cause of, the BrS substrate, which may create a hibernation-like state due to loss of contractility in the RVOT secondary to loss of the AP dome.
Structural changes–including mild fibrosis and reduced expression of Cx43 in RVOT or fibro-fatty infiltration in cases of ARVC. Imaging studies have also revealed wall motion abnormalities and mild dilatation in the region of the RVOT.	Higher in some forms of the syndrome	Unknown	Some investigators have hypothesized that some of these changes may be the result of, rather than the cause of, the BrS substrate, which may create a hibernation-like state due to loss of contractility in the RVOT secondary to loss of the AP dome.

RVOT=right ventricular outflow tract, AP=action potential; PVC=premature ventricular contraction

As will be discussed in more detail below, ERS and BrS also share similarities with respect to the response to pharmacological therapy. In both, electrical storms and associated J wave manifestations can be suppressed using β-adrenergic agonists.^115-118 Chronic oral pharmacological therapy using quinidine,^{119, 120} bepridil,¹¹⁷ denopamine,^{115, 121} and cilostazol^{115, 117, 121-125} is reported to suppress the development of VT/VF in both ERS and BrS secondary to inhibition of I_to, augmentation of I_Ca, or both.^{3, 122, 126}

Differences between the two syndromes include: 1) the region of the heart most affected (RVOT vs. inferior LV); 2) the presence of (discrete) structural abnormalities in BrS and not in ERS; 3) the incidence of late potentials in signal-averaged ECGs (SAECG: BrS [60%] > ERS [7%])¹⁰⁸; and 4) greater elevation of J_O, J_P or J_t (ST segment elevation) in response to sodium channel blockers in BrS vs. ERS and higher prevalence of atrial fibrillation in BrS vs. ERS.¹²⁷ Early studies suggested a different pathophysiological basis for ERS and BrS based on the observation that sodium channel blockers unmask or accentuate J wave manifestation in BrS, but reduces the amplitude in ERS.¹⁰⁸ The recent study by Nakagawa et al., however, showed that J waves recorded using unipolar LV epicardial leads introduced into the left lateral coronary vein in ERS patients are indeed augmented, even though J waves recorded in the lateral precordial leads are diminished, due principally to engulfment of the surface J wave by the widened QRS.^{29, 108} The case report of Nakagawa et al. has recently been supplemented with additional cases in which this technique was used; two of these three cases showed pilsicainide-induced accentuation of the J waves in electrograms recorded from the epicardial surface of the LV (Morita, unpublished observation). Also in support of the thesis that these ECG patterns and syndromes are closely related are reports of cases in which ERS transitions into ERS plus BrS.^{105, 128}

The principal difference between BrS and ERS has to do with the region of the ventricle most affected. Epicardial mapping studies in BrS patients report accentuated J waves, fragmented and/or late potentials in the epicardial region of the RVOT,^129-131 whereas in ERS, only accentuated J waves, particularly in the inferior wall of LV, are observed.²⁹ Fractionated electrogram activity and late potentials have been observed in experimental models of ERS,³⁰ but as yet have not been reported clinically. Non-invasive mapping electro-anatomical studies have reported very steep localized repolarization gradients across the inferior/lateral regions of LV of ERS patients, preceded by normal ventricular activation,¹³² whereas in BrS both slow, discontinuous conduction and steep dispersion of repolarization are present in the RVOT.¹³³ Another presumed difference is the presence of structural abnormalities in BrS, which as yet have not been described in ERS.⁷⁶

Although J waves are accentuated or induced by both hypothermia and fever,^{33, 34, 134-139} the development of arrhythmias in ERS is much more sensitive to hypothermia, and arrhythmogenesis in BrS appears to be promoted only by fever.^{33, 34, 138, 139} Hypothermia has been reported to increase the risk of VF in ERS,^{33, 34, 134, 135, 140} and fever is well recognized as a major risk factor in BrS.^{138, 139} It is noteworthy that hypothermia can diminish the manifestation of a BrS ECG when already present.^{141, 142}

An ER pattern is associated with an increased risk for VF in patients with acute myocardial infarction¹⁴³ and hypothermia.^{33, 144} A concomitant ER pattern in the infero-lateral leads has also been reported to be associated with an increased risk of arrhythmic events in patients with BrS. Kawata et al. reported that the prevalence of ER in infero-lateral leads was high (63%) in BrS patients with documented VF.¹⁴⁵

Genetics

BrS has been associated with variants in 18 genes (Table 7). To date, more than 300 BrS-related variants in SCN5A have been described^{21, 146-148} Figure 2 shows the overlap syndromes attributable to genetic defects in SCN5A. Loss-of-function mutations in SCN5A contribute to the development of both BrS and ERS, as well as to a variety of conduction diseases, Lenegre disease and Sick Sinus Syndrome. The available evidence suggests that the presence of a prominent I_to determines whether loss-of-function mutations resulting in a reduction in I_Na will manifest as BrS/ERS or as conduction disease.^{59, 149-151}

Table 7.

Gene defects associated with the Early Repolarization (ERS) and Brugada (BrS) Syndromes

Genetic Defects Associated with ERS
	Locus	Gene/Protein	Ion Channel	% of Probands
ERS1	12p11.23	KCNJ8, Kir6.1	↑IK-ATP	Rare
ERS2	12p13.3	CACNA1C, Cav1.2	↓ ICa	4.1%
ERS3	10p12.33	CACNB2b, Cavβ2b	↓ ICa	8.3%
ERS4	7q21.11	CACNA2D1, Cavα2σ1	↓ ICa	4.1%
ERS5	12p12.1	ABCC9, SUR2A	↑ IK-ATP	Rare
ERS6	3p21	SCN5A, Nav1.5	↓ INa	Rare
ERS7	3p22.2	SCN10A, Nav1.8	↓ INa	Rare
Genetic Defects Associated with BrS
	Locus	Gene/Protein	Ion Channel	% of Probands
BrS1	3p21	SCN5A, Nav1.5	↓ INa	11-28%
BrS2	3p24	GPD1L	↓ INa	Rare
BrS3	12p13.3	CACNA1C, Cav1.2	↓ ICa	6.6%
BrS4	10p12.33	CACNB2b, Cavβ2b	↓ ICa	4.8%
BrS5	19q13.1	SCN1B, Navβ1	↓ INa	1.1%
BrS6	11q13-14	KCNE3, MiRP2	↑ Ito	Rare
BrS7	11q23.3	SCN3B, Navβ3	↓ INa	Rare
BrS8	12p11.23	KCNJ8, Kir6.1	↑ IK-ATP	2%
BrS9	7q21.11	CACNA2D1, Cav α2σ1	↓ ICa	1.8%
BrS10	1p13.2	KCND3, Kv4.3	↑ Ito	Rare
BrS11	17p13.1	RANGRF, MOG1	↓ INa	Rare
BrS12	3p21.2-p14.3	SLMAP	↓ INa	Rare
BrS13	12p12.1	ABCC9, SUR2A	↑ IK-ATP	Rare
BrS14	11q23	SCN2B, Navβ2	↓ INa	Rare
BrS15	12p11	PKP2, Plakophillin-2	↓ INa	Rare
BrS16	3q28	FGF12, FHAF1	↓ INa	Rare
BrS17	3p22.2	SCN10A, Nav1.8	↓ INa	5-16.7%
BrS18	6q	HEY2 (transcriptional factor)	↑ INa	Rare

Listed in chronological order of their discovery

Figure 2.

Schematic showing the three categories of overlap syndromes resulting from genetic defects resulting in loss of function of sodium (I_Na) and/or calcium (I_Ca) channel current. In the absence of prominent I_to or I_K-ATP , loss-of-function mutations in the inward currents result in various manifestations of conduction disease. In the presence of prominent I_to or I_K-ATP , loss-of-function mutations in inward currents cause conduction disease as well as the J wave syndromes (Brugada and Early Repolarization Syndromes). Early Repolarization Syndrome is believed to be caused by loss-of-function mutations of inward current in the presence of prominent I_to in certain regions of the left ventricle (LV), particularly the inferior wall of the LV. The genetic defects that contribute to BrS and ERS can also contribute to the development of long QT and conduction system disease, in some cases causing multiple expressions of these overlap syndromes. In some cases, structural defects contribute to the phenotype.

Variants in CACNA1C (Cav1.2), CACNB2b (Cavß2b) and CACNA2D1 (Cavα2δ) have been reported in up to 13% of probands.^152-155 Mutations in glycerol-3-phophate dehydrogenase 1-like enzyme gene (GPD1L), SCN1B (β₁-subunit of Na channel), KCNE3 (MiRP2), SCN3B (β3-subunit of Na channel), KCNJ8 (Kir 6.1), KCND3 (Kv4.3), RANGRF (MOG1), SLMAP, ABCC9 (SUR2A), (Navß2), PKP2 (Plakophillin-2), FGF12 (FHAF1), HEY2, and SEMA3A (Semaphorin) are relatively rare.^156-176 An association of BrS with SCN10A, a neuronal sodium channel, was recently reported.^{167, 177, 178} A wide range of yields of variants were reported by the two studies that examined the prevalence of pathogenic SCN10A mutations and rare variants (5%-16.7%).^177-179 Mutations in these genes lead to loss of function in sodium (I_Na) and calcium (I_Ca) channel currents, as well as to a gain of function in transient outward potassium current (I_to) or ATP-sensitive potassium current (I_K-ATP).¹⁷⁸

New susceptibility genes recently proposed and awaiting confirmation include the Transient Receptor Potential Melastatin Protein 4 gene (TRPM4)¹⁸⁰ and the KCND2 gene. The mutation uncovered in KCND2 in a single patient was shown to cause a gain of function in I_to when heterologously expressed.¹⁸¹

Variants in KCNH2, KCNE5, SEMA3A, although not causative, have been identified as capable of modulating the substrate for the development of BrS.^182-185 Loss-of-function mutations in HCN4 causing a reduction in pacemaker current, I_f, can unmask BrS by reducing heart rate.¹⁸⁶

An ER pattern in the ECG has been shown to be familial.^187-189 The ER pattern and ERS have been associated with variants in 7 genes. Consistent with the findings that I_K-ATP activation can generate an ER pattern in canine ventricular wedge preparations, variants in KCNJ8 and ABCC9, responsible for the pore forming and ATP-sensing subunits of the I_K-ATP channel, have been reported in patients with ERS.^{156, 158, 190} Loss-of-function variations in the α1, β2 and α2δ subunits of the cardiac L-type calcium channel (CACNA1C, CACNB2, and CACNA2D1) and the 1subunit of Nav1.5 and Na_V1.8 (SCN5A and SCN10A) have been reported in patients with ERS.^{113, 152, 177}

It is important to point out that only a small fraction of identified genetic variants in the genes associated with BrS and ERS have been examined using functional expression studies to ascertain causality and establish a plausible contribution to pathogenesis. Only a handful have been studied in genetically engineered animal models, and very few have been studied in native cardiac cells or in induced pluripotent stem cell-derived cardiac myocytes isolated from ERS and BrS patients. Computational strategies developed to predict the functional consequences of mutations are helpful, but these methods have not been rigorously tested. The lack of functional or biological validation of mutation effects remains the most severe limitation of genetic test interpretation, as recently highlighted by Schwartz et al.¹⁹¹

Recent technological advances have resulted in expansion of disease-specific panels.¹⁹² Large public databases of genetic variation from next-generation sequencing programs such as the 1000 Genomes Project, the National Heart Lung and Blood Institute Grand Opportunity Exome Sequencing Project (GO-ESP), and the Exome Aggregation Consortium (ExAC), have challenged drastically our understanding of the “normal” burden and extent of background genetic variation within cardiac channelopathy-susceptibility genes.^193-195

Although SCN5A variants account for 18%-28% of BrS,¹⁹⁶ SCN5A genetic testing is complicated by a ~3%-5% “benign” variant frequency in the general population.¹⁹⁴ Therefore, even in the most common genetic cause of BrS, 1 in 10 “positive” tests could be a “false positive” even if found in an individual with a robust BrS phenotype. To date, there are over 20 J wave syndrome (JWS)-susceptibility genes.^{146, 195, 197} However, these additional genes have only magnified the issues of interpretation by adding to the overall “genetic noise,” without significantly increasing the true mutation yield.^{178, 198-200} In fact, one study revealed that 1:23 individuals in the GO-ESP population possess a previously published BrS-associated variant that would prompt a “positive” genetic test had it been identified in a patient.²⁰¹

These issues reinforce the necessity to interpret JWS genetic test results as strictly probabilistic, rather than binary/deterministic, in nature. Additional lines of evidence²⁰² can be amassed to aid in the probabilistic interpretation of variants in JWS-susceptibility genes such as case phenotype,²⁰³ segregation, functional studies,²⁰⁴ in silico predictions,^205-208 variant type and location,¹⁹⁴ and variant frequency in cases and control databases.¹⁹³ Despite these aids, a large number of variants remain in “genetic purgatory,” and this number will only increase as the use of exome/genome sequencing becomes more utilized. This then demands the development and utilization of a uniform variant repository that would include clinical assertions and evidence for variant classification. Even with these issues, the emergence of exome/genome sequencing holds promise for the opportunity to study genetic variation like never before, holding the promise of improvements in diagnostic, prognostic, and therapeutics for the JWSs and the other heritable cardiac channelopathies. Kapplinger et al. recently reported the synergistic use of up to 7 in silico tools to help promote or demote a variant’s pathogenic status and alter its relegation to genetic purgatory.²⁰⁹

It is noteworthy that in a recent study Le Scouarnec and colleagues estimated the burden of rare coding variation in arrhythmia-susceptibility genes among 167 BrS index patients and compared that with 167 individuals 65 years old and older with no history of cardiac arrhythmia.¹⁹⁹ The authors concluded that, except for SCN5A, rare coding variations in all previously reported BrS-susceptibility genes do not contribute significantly to the occurrence of BrS in a population with European ancestry, emphasizing that caution should be taken when interpreting genetic variations in these other genes because rare coding variants are observed to a similar extent in both cases and controls.¹⁹⁹ Similar data were obtained and a similar conclusion was reached by Kapplinger et al., by analyzing the prevalence of rare variants in the BrS-susceptibility genes in the publicly available ExAC exomes.²⁰⁹

Collectively, these data suggest the possibility that. in the individual patient, BrS and the susceptibility to VF and SCD may not be due to a single mutation (classical Mendelian view), but rather to inheritance of multiple BrS-susceptibility variants (oligogenic) acting in concert through one or more mechanistic pathways.¹⁶⁷ This also fits with the findings of Probst et al. that in 5 out of 13 large families with a putative SCN5A mutation, the genotype did not co-segregate with the phenotype.²¹⁰ In addition to the multifactorial nature of the genetics, expressivity of the syndrome may be multifactorial in that the genetic predisposition can be modulated by hormonal (testosterone,^{211, 212} thyroxine²¹³) and other environmental factors, as well as morphological changes (fibrosis).⁷⁶

Update on the ionic and cellular mechanisms underlying BrS and ERS

The J wave syndromes are so named because they involve accentuation of the electrocardiographic J wave. Experimental evidence indicates that the J wave is inscribed as a consequence of a transmural voltage gradient caused by the manifestation of an AP notch in epicardium but not endocardium due to a heterogeneous transmural distribution of I_to.¹⁰⁴ An end of QRS notch, resembling a J wave, has been proposed to be due to intra-ventricular conduction delays. The two ECG manifestations can be distinguished on the basis of their response to rate, with the latter showing accentuation at faster rates.^{24, 59}

The cellular mechanisms underlying JWS have long been a matter of debate.^{214, 215} In the case of BrS, two principal hypotheses have been advanced: 1) The repolarization hypothesis asserts that an outward shift in the balance of currents in right ventricular epicardium can lead to repolarization abnormalities resulting in the development of phase 2 reentry, which generates closely coupled premature beats capable of precipitating VT/VF; and 2) The depolarization hypothesis suggests that slow conduction in the RVOT, secondary to fibrosis, reduced Cx43 leading to discontinuities in conduction, plays a primary role in the development of the electrocardiographic and arrhythmic manifestations of the syndrome. Conduction slowing is not necessarily limited to the RVOT area. Some investigators have postulated that changes in ion channel current responsible for BrS (i.e., loss of function I_Na and I_Ca and gain of function of I_to) can alter AP morphology so as to reduce the safety of conduction at high-resistance junctions, such as regions of extensive fibrosis.^{216, 217} Others have argued that this is highly unlikely because conduction at critical junctions of current-to-load mismatch is exquisitely sensitive to changes in rate. The typical behavior of patients with BrS to acceleration of rate is diminution of ST segment elevation, opposite to that expected at a site of discontinuous conduction. The diminution of ST segment elevation is consistent with the reduced availability of I_to at the faster rate due to slow recovery of the current from inactivation.^{59, 214} The repolarization and depolarization theories are not necessarily mutually exclusive and may indeed be synergistic.

The most compelling apparent evidence in support of the depolarization hypothesis derives from the seminal studies of Nademanee et al.¹²⁹ showing that radiofrequency ablation (RFA) of epicardial sites displaying late potentials and fractionated bipolar electrograms (EGs) in the RVOT of patients with BrS significantly reduced the arrhythmia-vulnerability as well as the ECG-manifestation of the syndrome. Similar results were reported by Brugada et al.,¹³¹ and in an isolated case by Sacher and co-workers,¹³⁰ who also observed that accentuation of the Brugada ECG by ajmaline was associated with increasing area of low-voltage and fragmented electrogram activity. A wider area of low-voltage activity was associated with a more prominent ST-segment elevation.¹³¹ These authors concluded that the late potential and fractionated electrogram activity are due to conduction delays within the RVOT/RV anterior wall and that ablation of the sites of slow conduction is the basis for the ameliorative effect of ablation therapy.^129-131 In a direct test of this hypothesis, Szel and Antzelevitch¹⁵⁰ provided evidence for an alternative mechanism using an experimental model of BrS. The low-voltage fractionated electrogram activity was shown to develop due to regional desynchronization in the appearance of the second AP upstroke, secondary to accentuation of the epicardial AP notch, and high-frequency late potentials develop in the RV epicardium secondary to concealed phase 2 reentry. Delayed conduction of the primary beat was never observed in a wide variety of BrS models created by exposing canine right ventricular wedge preparations to drugs mimicking the different genetic defects known to give rise to BrS.¹⁵⁰ In more recent studies, ablation of the RV epicardium was shown to diminish the manifestation of J waves and ST segment elevation and to abolish all arrhythmic activity by destroying the cells with the most prominent AP notch, thus eliminating the cells responsible for the repolarization abnormalities that give rise to phase 2 reentry and VT/VF.^{15, 218} Confirmation of all of the above results in in vivo animal models is desirable. In an attempt to create such a model, Park et al. recently genetically engineered Yucatan minipigs to heterozygously express a nonsense mutation in SCN5A (E558X) originally identified in a child with BrS.¹⁴⁹ Patch clamp analysis of atrial myocytes isolated from the SCN5A^E558X/+ pigs showed a loss of function of I_Na. Conduction abnormalities consisting of prolongation of P wave, QRS complex and PR interval were observed, but a BrS phenotype was not observed, not even after the administration of flecainide. These observations are expected owing to the lack of I_to in the pig, which is a prerequisite for the development of the repolarization abnormalities associated with BrS. Some have argued that the absence of a BrS phenotype is due to the young age of the minipigs (22 months).²¹⁹ It is however difficult to reconcile why the minipigs manifest major conduction delays at this age but not a BrS phenotype, if indeed the latter depends on the former. Finally, it is noteworthy that monophasic APs recorded from the epicardial and endocardial surfaces of the RVOT of a patient with BrS are nearly identical to transmembrane APs recorded from the epicardial and endocardial surfaces of the wedge model of BrS.^{220, 221} These differences were not observed in an isolated heart explanted from a BrS patient after transplantation of a new heart. However, the epicardium of this heart was very depressed, perhaps as a result of the 129 shocks delivered by the ICD in an attempt to control the multiple electrical storms.³²

Zhang et al. recently performed noninvasive ECG imaging (ECGI) on 25 BrS and 6 RBBB patients.¹³³ The authors concluded that both slow, discontinuous conduction and steep dispersion of repolarization are present in the right ventricular outflow tract of patients with BrS. ECGI was able to differentiate between BrS and RBBB. Unlike BrS, RBBB showed delayed activation in the entire right ventricle, without ST-segment elevation, fractionation, or repolarization abnormalities showing on the electrograms. Importantly, in 6 BrS patients the response to an increase in rate was studied. Increasing rate increased fractionation of the electrogram but reduced ST-segment elevation, indicating that the conduction impairment was not the principal cause of the BrS ECG.

The congruence between BrS and ERS with respect to clinical manifestations and response to therapy lend further support for the repolarization hypothesis. Using an experimental model of ERS, Koncz et al.³⁰ recently provided evidence in support of the hypothesis that, similar to the mechanism operative in BrS, an accentuation of transmural gradients in the LV wall are responsible for the repolarization abnormalities underlying ERS, giving rise to J point elevation, distinct J waves, or slurring of the terminal part of the QRS. The repolarization defect is accentuated by cholinergic agonists and reduced by quinidine, isoproterenol, cilostazol and milrinone, accounting for the ability of these agents to reverse the repolarization abnormalities responsible for ERS.^{30, 222} Higher intrinsic levels of I_to in the inferior LV were also shown to underlie the greater vulnerability of the inferior LV wall to VT/VF.³⁰ The advent and implementation of electrocardiographic imaging (ECGI) by Rudy and colleagues provided additional evidence for repolarization abnormalities by identifying abnormally short activation-recovery intervals in the inferior and lateral regions of LV and a marked dispersion of repolarization.¹³² More recent studies involving ECGI mapping in an ERS patient during VF have demonstrated VF rotors anchored in the inferior-lateral left ventricular wall.²²

Conduction delays are known to give rise to notching of the QRS complex. When it occurs on the rising phase of the R wave, it is due to a conduction defect within the ventricle. When it occurs at the terminal portion of the QRS, thus masquerading as a J wave, it may be due either to a conduction or repolarization defect.^{21, 223} The response to prematurity or to an increase in rate can differentiate between the two.⁵⁹ Delayed conduction invariably becomes more exaggerated at faster rates or during premature beats, thus leading to an accentuation of the QRS notch, whereas repolarization defects are usually mitigated resulting in a diminution of the J wave at faster rates. Although typical J waves are usually accentuated with bradycardia or long pauses, the opposite has also been described.^{224, 225} J waves are often seen in young males with no apparent structural heart diseases, whereas intra-ventricular conduction delay is often observed in older individuals or those with a history of myocardial infarction or cardiomyopathy.^{223, 224} The prognostic value of a fragmented QRS has been demonstrated in BrS,^{49, 226} although fragmentation of the QRS is not associated with increased risk in the absence of cardiac disease.²²⁷ Factors that may aid in the differential diagnosis of J wave vs. IVCD-mediated syndromes are summarized in Table 8.

Table 8.

Differential diagnosis of J wave vs. Intra-ventricular Conduction Defect-mediated Notch Syndromes (IVCD)

	J wave	IVCD-induced end QRS notch
Male Predominance	Yes	No
Average Age at Initial Presentation	Young adults	Older adults
Most common Morphology	Dome-like smooth appearance	Relatively sharp appearance
Response to Change in Heart Rate	Bradycardia- and pause-dependent augmentation of J wave, which may be accompanied by T wave inversion	Tachycardia and prematurity-dependent augmentation of the notch
Structural Heart Diseases	Rare	Common History of myocardial infarction and/or cardiomyopathy

Risk stratification of the J wave syndromes

A great deal of attention has been devoted to risk assessment for the development of life-threatening arrhythmias in BrS and ERS.^{1, 228} The incidental discovery of a J wave on routine screening should not be interpreted as a marker of “high risk” for SCD since the odds for this fatal disease are approximately 1:10,000.²²⁹ Rosso et al. indicated that the presence of a J wave on the ECG increases the probability of VF from 3.4:100,000 to 11:100,000.^{4, 230} However, careful attention needs to be paid to subjects with “high risk” ER or J waves. Figure 4 presents a graphic representation of the prevalence and arrhythmic risk associated with the appearance of ECG J waves and clinical manifestations of BrS and ERS. Tables 9-11 present the available data from studies designed to identify patients at high risk for BrS and ERS. Among these risk stratifiers, some are highly predictive, including: 1) history of cardiac events or syncope likely due to VT/VF, and 2) prominent J waves in global leads including Type 1 ST segment elevation in the right precordial leads (Figure 5).

Figure 4.

Prevalence and arrhythmic risk associated with the appearance of ECG J waves and clinical manifestations of Brugada and Early Repolarization syndromes. The yellow highlighted region estimates the prevalence of the J wave syndromes. J waves in the lateral ECG leads have a high prevalence but are associated with a very low arrhythmic risk in a relatively small fraction of the cohort of individuals displaying J waves. On the other extreme, J waves appearing globally in the ECG have a very low prevalence, but are associated with a very high level of arrhythmic risk in a large fraction of the cohort presenting with J waves. Likewise, individuals displaying rapidly ascending ST segment elevation have a high prevalence but low risk, whereas subjects resuscitated from cardiac arrest have a very low prevalence by the highest level of arrhythmic risk.

TABLE 9.

Clinical variables associated with an increased risk of major arrhythmic events in Brugada Syndrome^*

Variable	Pts N	Prevention	Study end-point	Multivariable analysis HR (95% CI), p	Reference
History
Previous VF	93	P/S	SD, cardiac arrest or sustained VT/VF (N=25)	N/A (N/A), 0.005	MakimotoR292
Cardiac arrest	1029	P/S	SD (N=7), appropriate ICD shocks (N=44) or sustained VT/VF (N=0)	11 (4.8-24.3), 0.001	ProbstR359
Syncope or cardiac arrest	460	P/S	VF or SD (N=38)	12.7 (4.5-53.4), <0.0001	TakagiR360
Syncope of unknown origin	547	P	SD (N=16), VF (N=29)	2.5 (1.2-5.3), 0.017	BrugadaR361
Syncope	44	P/S	SCD (N=5), polymorphic VT or VF (recorded by ECG, Holter, or ICD) (N=7) or syncope of unknown etiology (11)	3.6 (1.09–11.7), 0.035	HuangR362
Syncope + spontaneous type 1 ECG	200	P/S	VF or SD from birth (N=22)	6.4 (1.9-21), <0.002	PrioriR363
Syncope of probable arrhythmic origin	1029	P/S	SD (N=7), appropriate ICD shocks (N=44) or sustained VT/VF (N=0)	3.4 (1.6-7.4), 0.002	KamakuraR364
Syncope	320	P	SD (N=3), appropriate ICD shocks (N=14) or sustained VT/VF (N=0)	2.8 (1.1-8.1), 0.03	DeliseR262
Syncope + spontaneous type 1 ECG	308	P	VF (N=1) or appropriate ICD intervention (N=13)	4.2 (1.4-12.8), 0.012	PrioriR49
Ventricular refractoriness
Ventricular refractory period <200ms	308	P	VF (N=1) or appropriate ICD intervention (N=13)	3.9 (1.03-12.8), 0.045	PrioriR49
ECG characteristics
Spontaneous type 1 ECG	1029	P/S	SD (N=7), appropriate ICD shocks (N=44) or sustained VT/VF (N=0)	1.8 (1.03-3.3), 0.04	ProbstR247
Spontaneous type 1 ECG	320	P	SD (N=3), appropriate ICD shocks (N=14) or sustained VT/VF (N=0)	6.2 (1.8-40), 0.002	DeliseR262
QRS fragmentation (2 or more spikes within the QRS complex in leads V1 to V3)	308	P	VF (N=1) or appropriate ICD intervention (N=13)	4.9 (1.5-1.8), 0.007	PrioriR49
Family history of sudden cardiac death at age 45 years	330	P	VF (N=56), syncope (N=67), or asymptomatic (N=207)	3.28 (1.4-7.6), 0.005	KamakuraR364
J wave in inferior and lateral leads	330	P	VF (N=56), syncope (N=67), or asymptomatic (N=207)	2.66 (1.1-6.7), 0.005	KamakuraR364
QRS duration > 90 ms in lead V2	460	P/S	VF or SD (N=38)	3.6 (1.4-12.2), 0.007	TakagiR360
Horizontal ST segment after J wave (ST-segment elevation ≤0.1 mV within 100 ms after J point and continued as a flat ST segment until the onset of the T-wave in ≥1 lead with J-wave)	460	P/S	VF or SD (N=38)	>10 (1.9-20.2), 0.02	TakagiR360
Late potentials (root mean square voltage of the terminal 40 ms of the filtered QRS complex <20μV + duration of low amplitude signals <40 μV of QRS in the terminal filtered QRS complex >38 ms)	44	P/S	SCD (N=5), polymorphic VT or VF (recorded by ECG, Holter, or ICD) (N=7) or syncope of unknown etiology (11)	10.9 (1.1–104), 0.038	HuangR362
ST-segment augmentation at early recovery of exercise test (ST-segment amplitude increase ≥0.05 mV in at least 1 of V1 to V3 leads at 1 to 4 min at recovery compared with the ST-segment amplitude at pre- exercise)	93	P/S	SD, cardiac arrest or sustained VT/VF (N=25).	N/A (N/A), 0.007	MakimotoR292

P=primary prevention patients only, P/S=primary and secondary prevention patients, SD=sudden death, VF=ventricular r fibrillation, VT=ventricular tachycardia

^*The list includes predictor variables that have been associated with an increased risk of major arrhythmic events (i.e, SCD, appropriate ICD interventions, or ICD therapy on fast VT/VF) in at least one published multivariable analysis in prospective studies.

TABLE 11.

Early repolarization patterns associated to idiopathic ventricular fibrillation, cardiac death or all causes mortality

Study design	Patient population	Early repolarization patterns	End-point	OR/HR*	Reference
Case- control	206 idiopathic VF 412 matched controls	J-point elevation ≥0.1 mV	Idiopathic VF	10.9 (6.3-18.9)	HaissaguerreR2
Case- control	45 idiopathic VF 124 matched controls 121 noncompetitive athletes	J-point elevation in inferior leads	Idiopathic VF	3.2 (1.4-7.5), p=0.006	RossoR4
		J-point elevation in I/aVL	Idiopathic VF	16.9 (2.0-140), p=0.009
		J-point elevation in V4-V6	Idiopathic VF	NS
Case- control	45 idiopathic VF 124 matched controls 121 noncompetitive athletes	J-point elevation	Idiopathic VF	4.0 (2.0-7.9)	RossoR245
		J-point elevation + horizontal ST-segment	Idiopathic VF	13.8 (5.1-37.2)
Case- control	21 athletes with idiopathic VF 365 controls athletes	J-point elevation ≥0.1 mV in infero-lateral leads	Idiopathic VF	4.63 (1.67-12.9), p=0.007	CappatoR366
		QRS slurring in any lead	Idiopathic VF	4.81 (1.73-13.4), p=0.007
Prospective	10,864 middle-aged people enrolled in the Finnish Social Insurance Institution’s Coronary Heart Disease Study (CHD study) between 1966 and 1972	J-point elevation ≥0.1 mV in inferior leads	Death from cardiac causes	1.28 (1.04-1.59) p=0.03	TikkanenR44
			Death from arrhythmias	1.43 (1.06-1.94) p=0.03
		J-point elevation ≥0.2 mV in inferior leads	Death from any cause	1.54 (1.06-2.24) p=0.03
			Death from cardiac causes	2.98 (1.85-4.92) p<0.001
			Death from arrhythmias	2.92 (1.45-5.89) p=0.01
Prospective	10,864 middle-aged people enrolled in the Finnish Social Insurance Institution’s Coronary Heart Disease Study (CHD study) between 1966 and 1972	J-point elevation ≥0.1 mV and horizontal/descending ST-segment	Sudden death	1.43 (1.05-1.94)	TikkanenR237
		J-point elevation ≥0.1 mV and upsloping ST-segment	Sudden death	NS
Prospective	1,161 middle-aged people enrolled in the 3rd French Monitoring Trends and Determinants in Cardiovascular Disease (MONICA) Project between 1994 and 1997	J-point elevation ≥0.1 mV	Total mortality	2.45 (1.44-4.15), p=0.001	RollinR236
			Cardiovascular mortality	5.6 (2.27-11.8), p=0.001
		J-point elevation ≥0.2 mV	Total mortality	NS
			Cardiovascular mortality	5.14 (1.72-15.4), p=0.004
		J-point elevation ≥0.1 mV in inferior leads	Total mortality	2.85 (1.62-5.02), p=0.001
			Cardiovascular mortality	5.28 (1.96-14.2), p=0.001
		J-point elevation ≥0.1 mV in lateral leads	Total mortality	NS
			Cardiovascular mortality	6.27 (1.85-21.3), p=0.003
		J-point elevation ≥0.1 mV and horizontal ST-segment elevation	Total mortality	3.04 (1.71-5.41), p=0.001
			Cardiovascular mortality	6.93 (2.75-17.4), p=0.001
		J-point elevation ≥0.1 mV and ascending ST-segment elevation	Total mortality	NS
			Cardiovascular mortality	NS
		J-point elevation ≥0.1 mV with notching pattern	Total mortality	3.11 (1.72-5.6), p=0.001
			Cardiovascular mortality	8.32 (3.32-20.8), p=0.001
		J-point elevation ≥0.1 mV with slurring pattern	Total mortality	NS
			Cardiovascular mortality	NS
Prospective	15,792 middle-aged biracial people enrolled in the U.S. Atherosclerosis Risk in Communities (ARIC) between 1987 and 1989	J-point elevation ≥0.1 mV in white men	Sudden death	NS	OlsonR238
			Coronary events	NS
			All cause mortality	NS
		J-point elevation ≥0.1 mV in white women	Sudden death	8.77 (3.19-24.13)
			Coronary events	NS
			All cause mortality	NS
		J-point elevation ≥0.1 mV in black men	Sudden death	NS
			Coronary events	NS
			All cause mortality	NS
		J-point elevation ≥0.1 mV in black women	Sudden death	NS
			Coronary events	1.47 (1.03-2.09)
			All cause mortality	NS
Prospective	29,281 subjects evaluated at the Palo Alto Veterans Affairs Hospital	J-point elevation >0.1 mV in black individuals	Cardiovascular death	NS	Perez-RieraR367
		J-point elevation >0.1 mV in non-black individuals	Cardiovascular death	1.6, p=0.02

^*adjusted OR/HR are reported when available

Figure 5.

Global Early Repolarization (Type 3 ER). J waves are apparent in the inferior, lateral and anterior (right precordial) leads.

Risk stratification of patients with ERS

The majority of the studies employing the criteria of Haissaguerre et al. for diagnosing the ER pattern ² have shown that ER, especially in the inferior ECG leads, predicts cardiac and arrhythmic death. Negative studies are few and may be attributable to exclusion criteria employed (e.g., atrial fibrillation, flutter, acute coronary syndrome), a relatively short follow-up period,^{231, 232} or different definitions of ER pattern.²³³ The recent consensus paper by Macfarlane et al. dealing with terminology of J wave-related phenomena in the setting of ER should enable us to avoid such confusion in the future.²⁴ The inclusion of Africans or African-Americans, in whom ER is prevalent but apparently not associated with high risk, may alter outcomes as well.²³⁴

Huikuri and colleagues reported in a series of seminal papers the results of a population-based study in Finland involving long-term prognosis of subjects with an ER pattern in the ECG.⁴⁴ Tikkanen et al. showed that J point elevation ≥ 0.1 mV was present in 5.8% of the population and that only 0.3% of the population had significant J point elevation ≥ 0.2 mV. J point elevation ≥ 0.1 mV in the inferior leads was associated with cardiovascular death (relative risk [RR]: 1.28) and arrhythmic death (RR: 1.43), and J point elevation ≥ 0.2 mV had a markedly elevated risk of death from cardiac causes (RR: 2.92) and from arrhythmia (RR: 2.92). Subsequent studies confirmed the association of J wave or ER with death from all causes, death from cardiovascular disease, sudden/unexpected death and death from arrhythmias.^{44-46, 127, 235-238} A horizontal or descending ST segment is associated with a worse prognosis than an ascending ST segment (Figure 3).^{237, 239} Individuals with a high amplitude J wave ≥ 0.2 mV followed by a horizontal or descending ST segment in the inferior/infero-lateral leads have a higher risk of lethal arrhythmias than those with a lower amplitude J-wave, especially those with a rapidly ascending ST segment following the J wave.

Figure 3.

Different manifestations of Early Repolarization. A. The J wave may be distinct or appear as a slur. In the latter case, part of the J wave is buried inside the QRS, resulting in an elevation of J_O. Patients with a distinct J wave have a worse prognosis than patients with a slurred J wave. B. The ST segment may be upsloping, horizontal or descending. Horizontal and descending ST segments are associated with a worse prognosis.

The appearance of J wave or ER is now recognized to predispose to the development of arrhythmogenesis when associated with other cardiac disorders, such as ischemia, heart failure and hypothermia. The J wave might predict prognosis of cardiac events in various heart diseases, and the appearance of a new J wave during acute ischemia seems to be a messenger of VF.^{240, 241}

Family history of sudden death in subjects with ER pattern has been identified as a risk factor.^{189, 242} The presence of co-existing Brugada ECG pattern (J waves in V1-V3) or short QT intervals in subjects with ER also suggests a more malignant nature.^{243, 244}

ER is commonly observed in the young, especially in fit and highly trained athletes ranging to a prevalence of up to 40%. In the majority of cases, the ensuing ST segment is rapidly ascending, suggesting that this is a benign ECG manifestation.^{237, 245}

Mahida and co-workers recently reported that electrophysiologic study using current programmed stimulation protocols do not enhance risk stratification in ER syndrome.²⁴⁶

Risk stratification of patients with BrS

Numerous studies consistently show that clinical presentation is the strongest predictor of risk in BrS, overshadowing all other risk factors. The risk of recurrent VF among patients presenting with cardiac arrest is considerable: ≈35% at 4 years, ^{247, 248} 44% at 7 years²⁴⁹ and 48% at 10 years.²⁵⁰ Fortunately, only a minority of BrS (6% in Europe ²⁴⁷ but 18% in Japan ²⁴⁸) diagnosed nowadays have a history of cardiac arrest.

Approximately one-third of contemporary BrS cohorts present with syncope.²⁴⁷ Their risk of arrhythmic events during followup is intermediate: approximately four times higher than the risk of asymptomatic patients^{49, 247, 251} but four times lower than that of patients diagnosed post-cardiac arrest.²⁴⁷ One explanation for this observation is that the syncope population consists of two different groups, one with arrhythmic syncope and bad prognosis, and a second group with vagal syncope and good prognosis. Although a detailed clinical history may be of great value in differentiating between these 2 groups, it is not infallible.²⁵² In reviewing the records of 342 BrS patients, Olde Nordkamp et al. ⁶⁰ concluded that arrhythmic and nonarrhythmic syncope can be distinguished by clinical characteristics, including the absence of prodromes and specific triggers. Compared to suspected non-arrhythmic syncope patients, patients presenting with presumed arrhythmic syncope were more likely to be male (relative risk 2.1), to have urinary incontinence (relative risk 4.6) and were less likely to report prodromes. They were also older at first event (45 vs. 20 years), and their syncope was never triggered by hot/crowded surroundings, pain or other emotional stress, sight of blood, or prolonged standing as in the case of non-arrhythmic syncope. During follow-up, all the spontaneous arrhythmic events occurred in patients originally presenting with presumed arrhythmic syncope; patients with benign syncope had an excellent long-term prognosis.

Asymptomatic patients represent a majority (~63%) of newly diagnosed Brugada patients today.^{247, 248} Their risk of developing symptoms is relatively low (0.5% per year).^{247, 248} Unfortunately, for most. the first symptom is cardiac arrest or sudden cardiac death. Therefore, risk stratification of asymptomatic patients is of utmost importance, and strategies for doing so are discussed below. In cardiac arrest patients or patients with presumed arrhythmic syncope, these strategies are of little use since they are recognized to be at high risk.

Age and gender

The mean age at the time of cardiac arrest in Brugada patients is 39-48 years, and the vast majority develop symptoms between 20 and 65 years of age. ^247-249 Asymptomatic elderly patients with Brugada syndrome are thought to be at a relatively low risk for future cardiac events.²⁵³ BrSin children is very rare, but sudden death in this population has been described.^{65, 254, 255} As in adults, cardiac arrest survivors are at high risk of recurrence, but data regarding risk stratification of asymptomatic children are limited. In large series, 64%-94% of patients with BrS presenting with cardiac arrest were male.^{247, 248, 250} Males are also at increased risk of displaying a spontaneous Type I Brugada ECG and of having inducible VF during electrophysiologic (EP) studies.¹⁰⁶ Nevertheless, because the majority of asymptomatic patients are also male, gender is not an independent predictor of arrhythmic events.^{106, 248}

Familial and genetic background

Neither family history of SCD nor the presence of a mutation (of any type) in the SCN5A gene have consistently been demonstrated to be of value in risk stratification.^247-249 One study, however, has shown that SCN5A mutations resulting in protein truncation do confer greater risk.²⁵⁶ Certain rare variants and polymorphisms in SCN5A and in other genes have also been associated with prognosis.^{167, 257-261} Nevertheless, the data are limited, and genetic testing is not generally used for risk stratification at this time.

Spontaneous vs. drug-induced Type I Brugada pattern

A consistent finding in nearly all BrS series is that patients with spontaneous Type I ECG at time of diagnosis have a greater risk of arrhythmic events than patients who develop such an ECG pattern only when challenged with a sodium channel blocker.^{247, 262} This observation is true for asymptomatic patients²⁴⁷ as well as patients presenting with syncope^{49, 247, 251, 263} and remains an independent predictor of arrhythmic events in multivariate analysis. The problem is that only a minority of patients have a consistent spontaneous Type 1 pattern when repeated ECGs are analyzed.^{264, 265} Therefore, caution should be employed when using a single ECG for risk stratification.

Ventricular arrhythmias are rarely induced during a sodium-channel-block challenge^{65, 262, 266, 267} and are likely to be dose-dependent (i.e., will not occur when the infusion is stopped for safety reasons prior to reaching the full dose). Their long-term prognostic significance remains unclear. Extra caution should be exercised when administering sodium channel blockers to patients with significant conduction disease.

Placing the right precordial leads over the 2^nd and 3^rd intercostal space, in addition to the standard 4^th intercostal space, increases the sensitivity for detecting the coved ST-segment elevation of the Type I Brugada pattern. Available data suggest that this increased detection of spontaneous Type I pattern does not affect the value of this parameter for predicting VF.^{52, 268, 269}

Electrophysiologic (EP) studies with programmed ventricular stimulation

The role of programmed ventricular stimulation during EP studies continues to be passionately debated.^270-272 The question is not whether VF inducibility correlates with arrhythmic risk; in all series, the VF inducibility rate is highest for cardiac-arrest survivors, intermediate for those with syncope and lowest for those asymptomatic at presentation.²⁷³ The central question is whether the prognostic information provided by VF inducibility is robust enough for clinical decision making. Some studies suggest that this is the case,^{262, 274, 275} but others do not.^{248, 249} One central issue suggested as an explanation for the discrepancy between studies is the extrastimulation protocol used. Specifically, the prognostic impact of site (RV apex vs. RV apex + RVOT)^{49, 270, 276} and number of extrastimuli (2 vs. 3) ^{49, 276} has been analyzed but with inconsistent results. The only prospective study specifically designed to examine the prognostic yield of EP studies in BrS was the PRELUDE registry.⁴⁹ It did not show that sustained VF induction identifies high-risk patients but did demonstrate that a short, effective ventricular refractory period (< 200 ms) is a risk marker.

Other risk markers

Several electrocardiographic markers have been associated with risk in BrS. These include: a) fragmentation of the QRS,^{226, 277, 278} b) the concomitant finding of a Type 1 Brugada pattern and an early repolarization pattern in infero-lateral leads^{145, 248, 279-281} and c) dynamic changes in the manifestation of prominent J waves or ST segment elevation.²⁸²

Other markers associated with increased risk but with limited or inconsistent data include: a) late potentials recorded using signal-averaged electrocardiography;^283-285b) microscopic T-wave alternans (TWA);²⁸⁶ c) macroscopic TWA during a sodium-blocker challenge test;^{285, 287, 288} d) increased QRS width;^{49, 248, 277, 289, 290} e) prominent R wave in aVR; ^289-291 and f) augmented ST-segment elevation of a Type 1 Brugada pattern during the recovery phase of an exercise test.²⁹² Prolonged Tpeak-Tend ^293-296 and relatively steep QT/RR slope have been associated with higher risk in cases of BrS.^{297, 298} Combining several risk factors (e.g.. fragmented QRS + ER pattern ²⁷⁷) appears to confer an additive risk, however, data supporting this are limited.

Update on approaches to therapy of BrS and ERS

Figures 6 and 7 graphically present recommendations for the management of BrS and ERS as modified from the 2013 HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes and the 2015 ESC Guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death.^{8, 9} Those recommendations are based on the available literature and on the clinical experience of members of the task force. As with all such recommendations they will need to undergo continuous validation by future studies.

Figure 6.

Indications for therapy of patients with Brugada syndrome. Recommendations with Class designations are taken from Priori SG, et al. HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes,⁸ and Priori SG, Blomstrom-Lundqvist C, Mazzanti A, et al. 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death.⁹ Recommendations without Class designations are derived from unanimous consensus of the authors.

ES= extrastimuli at RV apex, ICD=implantable cardioverter defibrillator. ILR=implantable loop recorder, NAR= nocturnal agonal respiration, VT=ventricular tachycardia

Figure 7.

Indications for therapy of patients with Early Repolarization Syndrome. Recommendations with Class designations are taken from Priori SG, et al. HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes. Heart Rhythm Dec 2013;10:1932-1963⁸ and Priori SG, Blomstrom-Lundqvist C, Mazzanti A, et al. 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Eur. Heart J Aug 29 2015 ⁹ Recommendations without Class designations are derived from unanimous consensus of the authors.

ER=early repolarization, ICD=implantable cardioverter defibrillator, ILR=implantable loop recorder, NAR=nocturnal agonal respiration, VT=ventricular tachycardia.

Education and lifestyle changes for the prevention of arrhythmias are critical in BrS. Patients should be informed of the various modulators and precipitating factors that could cause malignant arrhythmias. Fever should be treated aggressively with antipyretics, and contraindicated substances should be avoided (www.brugadadrugs.org).⁸⁹ Referral for ECG is recommended during high fever. Family members may be referred for CPR training and advised to consider purchase of an AED for home use. Because malignant ventricular arrhythmias are infrequent in asymptomatic patients with BrS²⁴⁷ or ER pattern⁴⁴ and usually unrelated to physical activity, the presence of these patterns does not contraindicate participation in sports.

It is noteworthy, however, that the Brugada pattern is accentuated immediately after exercise, due presumably to an increase in vagal tone. ^{292, 299, 300} In reviewing 98 case of BrS studies dealing with exercise, Masrur et al. concluded that there are insufficient data on the risks of exercise in BrS to make recommendations for exercise.²⁹⁹

Implantable Cardioverter Defibrillator

The only proven effective therapeutic strategy for the prevention of SCD in high risk BrS and ERS patients is an implantable cardioverter defibrillator (ICD).^{301, 302} It is important to recognize that ICDs are associated with complications, especially in young active individuals.^{249, 303} At 10 years post-implant, the rate of inappropriate shock and lead failure are 37% and 29%, respectively. Remote monitoring can identify lead failure and avoid inappropriate shocks.³⁰⁴ Sub-cutaneous ICDs are thought to represent the future for this indication in that they are expected to be associated with fewer complications over a lifetime.³⁰⁵

Implantation of an ICD is first-line therapy for JWS patients presenting with aborted SCD or documented VT/VF with or without syncope (Class I recommendation).^{301, 306} ICDs can be useful (Class IIa) in symptomatic BrS patients with Type 1 pattern, in whom syncope was likely caused by VT/VF. The HRS/EHRA/APHRS Expert Consensus states that ICD may be considered (Class IIb) in asymptomatic patients with inducible VF during programmed electrical stimulation (PES).⁸ Some studies suggest that the predictive value of EP studies may be improved by limiting the PES protocol to 2 extrastimuli,^{50, 276} but that observation is not supported by other studies. ^{49, 307} Similarly, some studies advocate that PES should be limited to the RVA and credit this limited PES strategy for a very high positive predictive value found is some series.²⁷⁵ Again, that observation is not confirmed by other studies.²⁷⁶

The current Task Force proposes that ICDs are reasonable (Class IIa) in symptomatic BrS patients with Type 1 pattern, but that implantation be considered on a case-by-case basis by an electrophysiologist experienced in BrS, taking into consideration age, gender, clinical presentation, ECG characteristics (QRS fragmentation, Jp amplitude) and patient’s preference. The current Task Force also proposes that electrophysiologic study may be considered in asymptomatic individuals with spontaneous Type 1 Brugada pattern. If VT/VF is inducible, an ICD should be considered.⁷ More recent studies argue in favor of using two or less extrastimuli to induce VT/VF.^{50, 276} ICDs are not indicated in asymptomatic patients without any of the above characteristics. At present, there is no clear role for PES in patients with ERS.

Pacemaker therapy

Arrhythmic events and sudden cardiac death in both BrS and ERS generally occur during sleep or at rest and are associated with slow heart rates. These observations notwithstanding, a potential therapeutic role for cardiac pacing remains largely unexplored.³⁰⁸ A few case reports are available.^{309, 310}

Radiofrequency Ablation Therapy

Nademanee et al.¹²⁹ showed that RFA of epicardial sites displaying late potentials and fractionated bipolar electrograms (EGs) in the RVOT of BrS patients can significantly reduce arrhythmia vulnerability and the ECG manifestation of the disease. Ablation at these sites was reported to render VT/VF non-inducible and to normalize the Brugada ECG pattern in the vast majority of patients over a period of weeks or months. Long-term follow-up (20±6months) showed no recurrent VT/VF, with only 1 patient on medical therapy with amiodarone. Case reports have been published in support of these effects.³¹¹ Additional evidence in support of the effectiveness of epicardial substrate ablation was provided by Sacher et al. and Shah et al.^{130, 312}

More recently, Brugada and co-workers used flecainide to identify the full extent of low voltage electrogram activity in the anterior RV and RVOT and targeted this region for RFA. In all, 14 BrS patients, RFA eliminated abnormal bipolar electrograms, normalized ST segment elevation on right precordial leads of ECG, and VT/VF was no longer inducible.¹³¹ Ablation therapy can be life-saving in otherwise uncontrollable cases. RF ablation may be considered (Class IIb recommendation) in BrS patients with frequent appropriate ICD-shocks due to recurrent electrical storms.⁷ There are no clinical reports of ablation of the LV substrate in patients with ERS. In patients in whom BrS combines with ERS, ablation of the anterior RV epicardium (including the RVOT) is not ameliorative.

Pharmacologic approach to therapy

Pharmacologic Approach to therapy of BrS

ICD implantation may be problematic in infants or young children due to the high complication rate. ICDs are also economically out of reach for patients in some regions of the world. A pharmacologic approach to therapy, based on a rebalancing of currents active during the early phases of the epicardial AP in the right ventricle so as to reduce the magnitude of the AP notch and/or restore the AP dome, has been a focus of basic and clinical research in recent years. Antiarrhythmic agents such as amiodarone and β blockers have been shown to be ineffective.³¹³ Class IC antiarrhythmic drugs (such as flecainide and propafenone) and class IA agents, such as procainamide, are contraindicated because of their effects to unmask BrS and induce arrhythmogenesis. Disopyramide is a class IA antiarrhythmic that has been demonstrated to normalize ST segment elevation in some Brugada patients but to unmask the syndrome in others.³¹⁴

Because the presence of a prominent I_to is a prerequisite for the development of both BrS and ERS, partial inhibition of this current is thought to be effective regardless of the ionic or genetic basis for the disease. Unfortunately, cardio-selective and I_to specific blockers are not available.

The only agent available in the United States and around the world with significant I_to blocking properties is quinidine.^{19, 73} Experimental studies have shown that quinidine is effective in restoring the epicardial AP dome, thus normalizing the ST segment and preventing phase 2 reentry and polymorphic VT in a variety of different experimental models of BrS.^{19, 150, 315-317}A recent experimental study suggests that quinidine, owing to its effect to block I_to, can also exert a protective effect against hypothermia-induced VT/VF in a J wave syndrome model.¹⁴⁴ It is noteworthy that, historically, quinidine was used to prevent ventricular fibrillation in patients who required hypothermia for surgical procedures.³¹⁷

Clinical evidence for the effectiveness of quinidine in normalizing ST segment elevation and/or preventing arrhythmic events in patients with BrS has been reported in numerous studies and case reports. ^{117, 119, 120, 124, 318-331} Hermida et al. reported 76% efficacy in prevention of VF induced by PES.¹¹⁹ Belhassen and colleagues³³² recently reported a 90% efficacy in prevention of VF induction following treatment with quinidine, despite the use of very aggressive protocols of extrastimulation. Furthermore, there were no arrhythmic events among BrS patients treated with quinidine during a mean follow-up period of 10 years.

In a recent trial conducted at two French centers, 44 asymptomatic BrS patients with inducible VT/VF were enrolled (47 ± 10 years, 95% male).³³³ Of these, 34 (77%) were no longer inducible while treated with 600 mg/day hydroquinidine (HQ) for 6.2 ± 3 years. Among the 10 other patients (22%), who remained inducible and received ICD (Group PVS+), none received appropriate therapy during a mean followup of 7.7 ± 2 years.

A prospective registry of empiric quinidine for asymptomatic BrS has been established. The study appears at the National Institutes of Health website (ClinicalTrials.gov) and can be accessed at http://clinicaltrials.gov/ct2/show/NCT00789165?term_brugada&rank_2. Doses between 600 and 900 mg were recommended, if tolerated.³²²

Quinidine may be considered (Class IIb indication) in BrS patients presenting with electrical storms and in patients implanted with an ICD and experiencing repeated appropriate shocks. Quinidine can also be useful in asymptomatic BrS patients displaying a spontaneous Type I ECG, if they qualify for an ICD and the device is refused or is contraindicated (Class IIa recommendation).

Agents that augment the L-type calcium channel current, such as β adrenergic agents like isoproterenol, denopamine or orciprenaline, are useful as well.^{19, 117, 121, 327, 334, 335} Isoproterenol, at times in combination with quinidine, has been utilized successfully to control VF storms and in normalizing ST elevation, particularly in children. 116, 319, 320, 331, 336, 337 93, 115, 117, 118, 279, 325, 338-343Spontaneous VF in patients with BrS is often related to increases in vagal tone and is amenable to treatment by an increase of sympathetic tone via isoproterenol administration. Administration of isoprotereonol is a Class IIa recommendation for BrS patients presenting with electrical storms.⁷

Another promising pharmacologic approach for BrS is the administration of phosphodiesterase III inhibitor cilostazol,^{117, 121, 123} which normalizes the ST segment, most likely by augmenting calcium current (I_Ca) as well as by reducing I_to secondary to an increase in cAMP and heart rate.³⁴⁴ Other effects of cilostazol may contribute to its actions (e.g., adenosine, NO, mitochondrial I_KATP ³⁴⁵). Its efficacy in combination with bepridil in preventing VF episodes was recently reported by Shinohara et al.¹²⁵ The failure of cilostazol in the treatment of BrS has been described in a single case report.³⁴⁶

Milrinone is another phosphodiesterase III inhibitor recently identified as a more potent alternative to cilostazol in suppressing ST elevation and arrhythmogenesis in an experimental model of BrS.^{150, 347} No clinical reports have appeared as yet.

Wenxin Keli, a traditional Chinese medicine has recently been shown to inhibit I_to and thus to suppress polymorphic VT in experimental models of BrS when combined with low concentrations of quinidine (5 μM).³¹⁶

Agents that augment peak and late I_Na, including bepridil and dimethyl lithospermate B (dmLSB), are suggested to be of value in BrS. Bepridil has been reported to suppress VT/VF in several studies of patients with BrS.^{117, 297, 298, 348} The drug’s action are thought to be mediated by: 1) inhibition of I_to; 2) augmentation of I_Na via up-regulation of the sodium channels³⁴⁹; and 3) prolongation of QT interval at slow rates thus increasing the QT/RR slope.^{297, 298} Dimethyl lithospermate B, an extract of Danshen, a traditional Chinese herbal remedy, has been reported to slow inactivation of I_Na, thus increasing I_Na during the early phases of the AP and suppressing arrhythmogenesis in experimental models of BrS.³⁵⁰

Because malignant ventricular arrhythmias are infrequent in asymptomatic patients with BrS²⁴⁷ or ER pattern⁴⁴ and usually unrelated to physical activity, the presence of these patterns does not contraindicate participation in sports, although as previously discussed, insufficient data are currently available to make definitive recommendations for participation in sports.

Approach to therapy of ERS

It is not surprising that the approach to therapy of ERS is similar to that of BrS, since the mechanisms underlying the two syndromes are potentially similar. Quinidine, phosphodiesterase III inhibitors and isoproterenol have all been shown to exert an ameliorative effect in preventing or quieting arrhythmias associated with ERS. Isoproterenol has been shown to be effective in quieting electrical storms developing in patients with either BrS^{117, 338} or ERS.¹⁹⁰ Isoproterenol has been shown to act by reversing the repolarization abnormalities responsible for the disease phenotype secondary to restoration of the epicardial AP dome in experimental models of both BrS^{19, 315} and ERS.³⁰ This action of the β adrenergic agonist is expected due to its actions to potently increase I_Ca.

The phosphodiesterase (PDE) III inhibitor cilostazol has been reported to reduce the ECG and arrhythmic manifestations of ERS.¹²² PDE inhibitors are known to activate I_Ca secondary to an increase in cAMP.^{121, 344, 351-355} The augmentation of I_Ca is thought to prevent arrhythmias associated with JWS by reversing the repolarization defects and restoring electrical homogeneity across the ventricular wall secondary to restoration of the epicardial AP dome in both BrS³⁴⁷ and ERS.¹⁴⁴ Cilostazol has been hypothesized to also block I_to. Augmentation of I_Ca together with inhibition of I_to are expected to produce an inward shift in the balance of currents active during the early phases of the epicardial AP that should be especially effective in suppressing J wave activity. The effectiveness of bepridil in ERS has been reported in a single patient thus far.³⁵⁶

No clinical data are available regarding the effectiveness of radiofrequency (RF) ablation in the setting of ERS, despite the fact that low-voltage fractionated electrogram activity and high-frequency late potentials are observed in the LV in patients with ERS³⁵⁷ and in experimental models of ERS (Yoon and Antzelevitch, unpublished observation). Nakagawa et al.³⁵⁷ reported the results of a study in which they recorded epicardial electrograms directly from the left ventricle of patients diagnosed with ERS by introducing a multipolar catheter into the left lateral (marginal) coronary vein, anterior interventricular vein , and middle cardiac vein (MCV) via the coronary sinus. The authors reported late potentials in the bipolar electrograms recorded from the LV epicardium of the ERS patients.³⁵⁷

TABLE 10.

Prognostic value of programmed ventricular stimulation resulting from multivariate analysis in large multicenter studies on Brugada syndrome

N.	Prevention	Inducibility %	Multivariable HR (95% CI), p	Reference
408	P	40%	5.88 (2.0-16.7), <0.001	BrugadaR365
308	P	41%	0.89 (0.3-2.6), 0.84	PrioriR49
638	P/S	62%	N/A, 0.48	ProbstR247
245	P	39%	Not tested on multivariable analysis, but an analysis based on C-statistics demonstrated that EPS results in combination with other risk factors provided additional value for risk stratification	DeliseR262
334	P/S	67%	0.63 (0.3-1.3), 0.20*	TakagiR360
1312*	P/S	42%	2.66 (1.44-4.92), 0.002	SroubekR50

P=primary prevention patients only, P/S=primary and secondary prevention patients

^*univariate analysis; not included in multivariable analysis

^*Pooled analysis from 8 international databases