Clinical Data and Suggested Pathophysiological Mechanism
The occurrence of ventricular fibrillation (VF) in the absence of any structural heart disease is classified as “primary electrical disease” or (in the absence of any relevant findings) “idiopathic VF.” This diagnosis implies that the arrhythmogenic substrate is inherent to the excitable and conducting properties of the heart. With the exception of a positive family history, demographic variables are, as a rule, not very helpful in establishing the diagnosis of primary electrical disease.1 The paradigm of primary electrical disease is the long-QT syndrome (LQTS), in which altered ionic channel function secondary to mutations in genes encoding ion channels has been shown to underlie QT-interval prolongation.2 3
In 1992, Brugada and Brugada4 described 8 patients with a history of aborted sudden death and a distinct ECG pattern, consisting of right bundle-branch block (RBBB) with ST-segment elevation in the right precordial leads (V1, V2, and V3, Figure 1⇓) and normal QT interval in the absence of any structural heart disease (as determined by routine clinical, biochemical, echocardiographic, and angiographic examinations). In 4 of the reported patients, a family history was suspected.
Patients with these unique ECG abnormalities have been recognized as a distinct subgroup in male Thai patients presenting with cardiac arrest due to VF.5 In northeastern Thailand, sudden unexpected death, typically occurring during sleep, is a leading cause of death in young men, and 40% of these patients have a family history of sudden death.6
The suspected inherited occurrence of the entity strongly suggested possible involvement of defective ion channels, as in LQTS. However, others have reported forms of right ventricular (RV) cardiomyopathy associated with the syndrome.7 8 The clinical data of the patients are crucial to the question of whether this syndrome is another “ion channelopathy” or a subclinical form of a more diffuse cardiomyopathy. This review aims to (1) summarize these clinical data and (2) speculate on the underlying pathophysiological mechanism. Finally, diagnostic guidelines will be proposed.
Patients with (aborted) sudden cardiac death and the “Brugada” ECG were described in the late 1980s.8 In a series of 6 patients successfully resuscitated from VF and without apparent structural heart disease, the typical ECG was recognized in 3 patients. In these patients, subclinical RV cardiomyopathy was postulated on the basis of results of RV biopsy in 1 patient and echocardiography in 2.8 In this and later reports, the authors consistently concluded that structural abnormalities underlie the syndrome.7 8 9 10
Brugada and Brugada4 were the first to speculate on a functional cardiac disorder. It was suggested that “Marked dispersion of refractoriness of cardiac tissue or extreme anisotropic conduction properties of the conduction system and the ventricular muscle” represented the underlying pathophysiological abnormality.4 The notion that the syndrome represents a “functional” disorder was further substantiated by the recognition that ECG abnormalities were inconsistently present11 12 13 and that altered autonomic tone5 13 and antiarrhythmic drugs modulated the extent of ST-segment elevation.11 13
The entity is increasingly recognized. In 1997, Brugada and Brugada11 reported on 47 patients, and the series has been extended to 63 patients in 1998.12 In a Japanese multicenter study, a further 63 patients were recognized, of whom 17 had a documented episode of VF.14 Kasanuki et al15 recognized the abnormal ECG pattern in 6 of 11 idiopathic VF subjects, and Nademanee et al5 recognized it in 16 of 27 Thai men resuscitated from VF. On the basis of pharmacological tests, it has been speculated that 40% to 60% of patients diagnosed with idiopathic VF might actually suffer the syndrome under discussion.16
To date, 108 symptomatic and 66 asymptomatic patients with the characteristic ECG consisting of right precordial ST-segment elevation with or without an RBBB pattern have been described (Table 1⇓). In 11 patients, some form of RV cardiomyopathy accounted for the ECG abnormalities.7 8 16 These patients are included in Table 1⇓ but are excluded from further analysis. Thus, 163 patients meet the criteria described by Brugada and Brugada.4
Males (n=150) outnumber females (n=13) by far (Table 1⇑), in contrast to the female preponderance of symptomatic LQTS. At least 95 patients (58%) were of Asian origin. Mean age at first arrhythmic event varied from 22 to 65 years. Age distribution reveals a peak around the fourth decade (range, 2 to 77 years).12 14 A family history of syncope, documented VF, or sudden death of suspected cardiac origin was reported for 36 patients (22%). In general, the patients’ medical histories were unremarkable.
By definition, the ECG was abnormal, displaying an RBBB pattern with right precordial ST-segment elevation (≥0.1 mV in leads V1 to V2 and V3). In most patients, however, the typical widened S wave in the left lateral leads is absent, suggesting that this is not true RBBB. Early high takeoff of the ST segment in the right precordial leads (the “J wave”) can mimic RBBB (Figure 2⇓).23 As can be derived from published tracings, in many patients, left axis deviation was present simultaneously, suggesting the presence of left anterior hemiblock as well (Figure 1⇑).
Descriptive or quantitative QTc data are reported as normal for all but 2 patients. In a 46-year-old man with a positive family history for sudden death, QTc was 488 ms,4 and in a 22-year-old man with an unremarkable family history, QTc was 500 ms.22
Two ST-segment morphologies have been described in leads V1, V2, and V3: convex curved or “coved” and “saddle shaped”–type ST-segment elevation.14 15 18 In individual patients, both morphologies may subsequently be present. The presence of coved ST-segment elevation has been suggested to have a stronger arrhythmogenic potential,14 18 but this relation could not be confirmed by others.15
Persistence of the abnormal ECG findings can last up to 40 years.27 Transient normalization seems to be common during follow-up; it may last up to 4 months and is unrelated to heart rate.11 With increasing heart rate, both ECG normalization5 15 18 and increasing J-wave amplitude have been reported.23
It is not clear whether the magnitude of the ST-segment shift relates to the occurrence of arrhythmias. In individual patients, the onset of polymorphic ventricular tachycardia (VT)/VF was preceded by ST-segment shifts,13 15 18 whereas in others it was not.23 24
Arrhythmia onset seems to be unlike that seen in LQTS. The coupling interval of the first ectopic beat to the preceding sinus beat is usually short (“R on T,” or in the terminal part of the T wave), and arrhythmia episodes are not preceded by particular R-R sequences.4 23 24
Among the 104 patients who presented with symptoms, VF was present in 76 (73%) and syncope in 28 (27%) (Table 1⇑). In the remaining 59 patients, the abnormal ECG was noted during routine ECG or screening because of sudden death of a family member. At presentation, none of the symptomatic patients were taking antiarrhythmic drugs or had electrolyte imbalances.
The activity at the moment of the arrhythmic event was reported for 21 patients. In at least 17 patients, it occurred while they were at rest or asleep; all of these patients were of Asian origin,5 13 15 18 20 21 26 and 9 were Thai men.5 In 4 patients, alcohol ingestion induced an arrhythmic event.
Echocardiography, Ventriculography, and Endomyocardial Biopsies
No echocardiographic evidence for structural cardiac abnormalities was found in 157 patients (Table 1⇑). Abnormal left and/or right ventriculography was reported for 2 of 80 patients (Table 1⇑). Nonspecific mild thickening of the moderator band was seen in 1,25 and hypokinesis of the left ventricular (LV) anterior wall was seen in the other.26 Endomyocardial biopsies were taken from 32 patients and were normal in all cases (Table 1⇑).
Magnetic Resonance Imaging
Normal echocardiographic findings and even normal ventricular endocardial biopsy findings do not exclude arrhythmic RV dysplasia (ARVD), because minor and/or localized forms may remain undiagnosed. In 1 of 35 patients in whom routine diagnostic methods showed no abnormalities, MRI demonstrated fatty replacement in the RV infundibulum, consistent with ARVD.17 This shows that MRI may be an important supplemental tool in the evaluation of these patients.17 28
To exclude ischemia as a causal arrhythmogenic factor, coronary angiography was performed in 82 patients (Table 1⇑), with normal results in all cases. In 65 of them, coronary spasm could not be induced by intracoronary ergonovine or acetylcholine injection. In 1 case, coronary artery spasm was induced, causing ST-segment elevation but not VF. Exclusion of ischemia by thallium scintigraphy has been reported in 3 patients only.4
Results of treadmill testing are available for 43 patients only.4 5 13 15 20 22 24 Exercise-induced ventricular arrhythmias did not occur, except in 1 patient, in whom a self-terminating monomorphic VT with LBBB configuration occurred at peak exercise.
Programmed electrical stimulation was performed in 76 patients (Table 2⇓). The HV interval was measured in 21 patients and was prolonged in 20. This observation is not typical for RBBB, and in conjunction with the left axis, in most published ECGs, it reflects a more general conduction defect in the His-Purkinje system.
In 58 patients, arrhythmic events were readily inducible. VF was induced in 50 patients and nonsustained polymorphic VT in 8 (Table 2⇑). Occasionally, VF was not inducible.12 13 18 24 In 2 patients, VF could not be induced in the baseline state but was inducible during administration of edrophonium in 1 patient15 and during administration of edrophonium and an α-adrenergic receptor agonist in another.13
Both theoretical considerations and in vivo experiments support the idea that heterogeneity of repolarization across the wall of the RV outflow tract (RVOT) contribute to the ECG patterns and the genesis of arrhythmias in the Brugada syndrome.
In contrast to endocardial cells, action potentials (APs) of epicardial cells display a pronounced phase 1 (Figure 3⇓), referred to as “spike-and-dome morphology.” The transient outward current, Ito, present in epicardial cells and virtually absent in endocardial cells, underlies the difference between the AP configurations.29
The spike-and-dome morphology is the result of at least 3 different currents: INa, Ito, and L-type calcium current, ICa. The magnitude and duration of sodium current, INa, during phase 0 determines the voltage level at which phase 1 begins. This will have an impact on activation/inactivation characteristics of Ito directly and of L-type ICa indirectly. Perturbations in these (or perhaps other, eg, ICl) currents can lead to striking abbreviation of the epicardial AP, with the resultant potential for reexcitation based on epicardial-endocardial heterogeneity of repolarization.
In an experimental model, the spike-and-dome configuration of APs coincides with J waves in the surface ECG. Loss of AP dome in epicardial cells but not endocardial cells may cause transmural heterogeneity and ST-segment elevation as a result of transmural current flow from endocardium to epicardium (Figure 3⇑).30 It can be hypothesized that, because of the thinness of the RV wall, the relative contribution of epicardial APs to the surface ECG is more prominent in right than left precordial leads. In addition, it has been demonstrated in dogs that the Ito-mediated phase 1 is more pronounced in RV than LV epicardium.31 Hence, the impact of changes in epicardial AP morphology will be most pronounced in precordial leads V1 and V2 facing the RVOT.
Theoretically, a reduction in INa or L-type ICa or an increase in Ito and/or addition of any other time-independent potassium current may cause the above-described changes. Experiments in canine heart lend further support to the idea that epicardial-endocardial heterogeneity causes the arrhythmias. Sodium channel blockers reduce phase 0 amplitude. The presence of Ito will subsequently depress phase 1 nadir and availability of L-type ICa will be diminished, leading to instantaneous all-or-non repolarization.32 Indeed, flecainide causes marked abbreviation of canine epicardial but not endocardial AP duration due to loss of AP dome. Thereby, flecainide causes electrical heterogeneity and phase 2 reexcitation.32
These findings are consistent with the reported effects of sodium channel blocking drugs in patients with the Brugada syndrome. Treatment with class Ia activated-state blockers (disopyramide, procainamide, flecainide, and ajmaline) increased ST-segment elevation (Figure 4⇓).5 11 13 Treatment with class Ib antiarrhythmic drugs (mexiletine and lidocaine) had no effect on ST-segment elevation.13 Administration of the class Ia antiarrhythmic drugs ajmaline and procainamide reproduced the abnormal ECG both in patients with transient normalized ECGs and in family members of affected individuals with a normal ECG.11
There are also profound effects of autonomic stimulation or suppression in these patients.13 33 β-Adrenergic stimulation might be expected to reduce electrical heterogeneity by augmenting L-type ICa, which restores epicardial AP dome. Indeed, both physiological and pharmacological β-adrenergic stimulation consistently reduced and β-adrenergic receptor blockade increased right precordial ST-segment elevation.5 13 15 Enhanced ST-segment elevation was also observed after α-adrenergic and muscarinic stimulation.13 15 The effect of α-adrenergic agonists was mitigated by α-adrenergic antagonists.13 The way in which these latter interventions modulate the amplitude of Ito, INa, or L-type ICa in epicardial versus endocardial cells is still being worked out.
An alternative hypothesis for the genesis of the arrhythmia is based on data from signal-averaged ECG and body-surface mapping. These data show conduction delay in the area between the anterior wall and the septal region of the RVOT, which is aggravated by accelerated vagal activity.15 Independent of the presence of a spike-and-dome morphology, significant epicardial conduction delay may give rise to the J wave as well. To explain ST-segment elevation, however, substantial shortening of the epicardial AP is needed. This alternative explanation for the ECG abnormalities may help to explain the preferential occurrence of nocturnal VF episodes.
Clinical Course and Therapy
Therapy is documented in 105 patients. Seventy-five patients did not receive pharmacological treatment. In 54 of them, an implantable cardioverter-defibrillator (ICD) was implanted; 21 patients did not receive any form of therapy. In 31 of these patients (40%), arrhythmic events recurred during follow-up. In all 23 events occurring in patients with an ICD implanted, the device effectively terminated VF. However, in the 21 patients who did not receive any form of therapy, 8 arrhythmic events resulted in 7 deaths (Table 2⇑).
Treatment with antiarrhythmic drugs did not effectively prevent new events. Thirty patients were treated with either β-adrenergic receptor blockade (n=9), amiodarone (n=4), sodium channel blockade (n=1), a combination of β-adrenergic receptor blockade with amiodarone (n=15), or α-blockade (n=1). Arrhythmic events recurred in 9 patients (30%), causing 7 deaths (Table 2⇑).
Thus, irrespective of the underlying mechanism, RBBB with right precordial ST-segment elevation identifies patients at risk for VF. From the reviewed data, no particular antiarrhythmic drug emerges that seems useful in preventing new episodes of VF. β-Adrenergic receptor blockade even seems to be contraindicated.15 On a theoretical basis, quinidine, a vagolytic drug that blocks Ito, among other potassium currents, may prove to be of benefit. Interestingly, quinidine has been demonstrated to exert antiarrhythmic potency in patients with idiopathic VF, of whom some may actually suffer from Brugada’s syndrome.34
Only an ICD effectively prevents sudden death.5 12 Transient normalization of the ECG abnormalities does not decrease the need for therapy. Based on the preferential occurrence of nocturnal arrhythmic events and enhanced vagal activity during sleep, pacemaker implantation might be prudent.
Molecular Biological Background
The proposed underlying mechanisms of the syndrome suggest that mutations in the genes encoding the cardiac sodium channels, the transient outward channels, and/or calcium channels are candidates to explain the hereditary transmission of the disease.
Mutations have been identified in the cardiac sodium channel gene (SCN5A) in 3 small families and individual patients with a history of VF in the presence of the described ECG abnormalities.16 35 Although these initial data have not yet provided a complete explanation for the manifestations of the disease and lack genetic linkage, they form a very encouraging first step for future research.
The cardiac sodium channel α-subunit consists of 4 domains (D-I through D-IV), each containing 6 transmembrane-spanning segments (S1 through S6). In 1 family, 2 single nucleotide missense mutations were identified (R1232W and T1620M) in the extracellular loops of DIII (S1-S2) and DIV (S3-S4), respectively.16 Unlike the SCN5A mutations associated with LQTS,36 expression of T1620M showed no persistent inactivation-resistant currents but faster recovery from inactivation. R1232W behaves like normal channels and probably constitutes a rare polymorphism.
In a second family, insertion of 2 nucleotides disrupted a splice-donor site within the intracellular loop between S2 and S3 of D-I. Functional consequences of this splicing mutation have not been studied.16
In a third family, a single nucleotide deletion introduced a premature in-frame stop codon in DIII S6. Mutant mRNA failed to express INa in Xenopus oocytes.16 This finding suggests that affected patients would have a 50% reduction of sodium channels. However, this is a huge decrease, so preferential expression of the normal allele seems possible.
In individual patients, we report missense mutations (R1512W in the highly conserved DIII-IV cytoplasmic linker and A1924T in the C-terminal cytoplasmic domain).35 Preliminary data demonstrate that both mutations affect channel function, most notably causing a negative voltage shift of the steady-state activation curve.37
A loss of functional sodium channels, which is suggested to result from the disrupted splice-donor site,16 results in less INa. Pharmacological inhibition of INa has been shown to cause less AP dome and phase 2 reexcitation.32 In contrast, the mentioned alterations in sodium channel characteristics will enhance availability of sodium channels and/or INa and is therefore difficult to reconcile with the discussed underlying electrophysiological basis of the syndrome.
Brugada and Brugada4 are to be credited for recognizing a distinct subgroup of patients with idiopathic VF. These patients are electrocardiographically characterized by the presence of an RBBB pattern or J wave and right precordial ST-segment elevation ≥0.1 mV. Absence of organic heart disease is demonstrated by echocardiography, ventriculography, MRI, and RV endomyocardial biopsies and can be inferred from the occurrence of transient ECG normalization. Administration of the class I antiarrhythmic drugs ajmaline or procainamide reproduces the abnormal ECG in patients with transient normalized ECGs and in family members of affected individuals with normal ECGs.11 Patients are mostly male and have a first arrhythmic event around their fourth decade. The recurrence rate of new arrhythmic events is as high as 40%. Pharmacological treatment does not protect effectively against recurrent events, and currently, implantation of an ICD is the only effective therapy to prevent sudden death.
Therefore, not least because of cost-effectiveness, an unequivocal diagnostic definition of this life-threatening syndrome is needed. In our opinion, at least the following diagnostic criteria should be met: (1) ≥0.1-mV ST-segment elevation in leads V1, V2, and V34 ; (2) absence of organic heart disease4 ; (3) dynamic nature of the ST segment, both spontaneously in time and under the influence of pharmacological agents (sodium channel blockers and autonomic modulators); and (4) malignant family history in the case of an asymptomatic individual.
Given the occurrence of transient ECG normalization, we recommend challenge with sodium channel blockers (procainamide, ajmaline, or flecainide in therapeutic dosages) in asymptomatic family members. The occurrence of ≥0.1-mV ST-segment elevation in leads V1, V2, and V3 is regarded as a positive response. Current data do not allow us to define the prevalence of asymptomatic syndrome carriers or to draw conclusions about their treatment. However, we would suggest that additional studies be performed, including programmed electrical stimulation, in asymptomatic young to middle-aged (especially male) individuals without a malignant family history. In the case of inducible VF, an ICD should be implanted. In asymptomatic individuals with a malignant family history, the threshold for ICD implantation should be low, regardless of electrophysiology results. In general, the role of quinidine remains to be established.
There is little doubt that major advances in further unraveling the molecular mechanism of this syndrome will occur in the near future.
Dr Alings is the recipient of an Interuniversity Cardiology Institute Netherlands fellowship. Dr Wilde is a Clinical Investigator for the Netherlands Heart Foundation (grant D95/014). Dr Dan Roden (Vanderbilt University, Nashville, Tenn) is gratefully acknowledged for his critical reading of the manuscript.
- Received June 19, 1998.
- Revision received October 6, 1998.
- Accepted October 22, 1998.
- Copyright © 1999 by American Heart Association
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