Clinical, Genetic, Molecular and Cellular Aspects of the Brugada Syndrome –
A Paradigm for Understanding the Role of Spatial Dispersion of Repolarization in Arrhythmogenesis

Charles Antzelevitch

Masonic Medical Research Laboratory, Utica, NY, USA

Correspondence: Dr. Charles Antzelevitch, Masonic Medical Research Laboratory, 2150 Bleecker Street, Utica, NY 13501 USA.
E-mail: ca@mmrl.edu

1.    Introduction

In 1986, a 3-year-old Polish boy was referred to the Brugada brothers after multiple episodes of syncope. His ECG showed an ST segment elevation in leads V₁-V₃. His sister had died at 2 years of age. In the succeeding years, six additional cases, came to their attention and in 1992 Pedro and Josep Brugada reported these 8 cases as the basis for a new and distinct clinical entity. (Brugada & Brugada, 1992) The syndrome is characterized by an ST segment elevation in the right precordial ECG leads and a high incidence of sudden death in patients with structurally normal hearts

In 1996, Yan and Antzelevitch (Yan & Antzelevitch, 1996) in their publication on the cellular basis for the J wave pointed out the importance of the ST segment elevation (accentuated J wave) and apparent right bundle branch block described by Brugada and Brugada as the basis for a substrate capable of giving rise to malignant arrhythmias, and name it the “Brugada Syndrome”. Kobayashi et al (Kobayashi et al., 1996) and Miyazaki et al. (Miyazaki et al., 1996) followed suit that same year.

The electrocardiographic features of the Brugada syndrome include 1) an accentuated J wave appearing principally in the right precordial leads (V1-V3) and taking the form of an ST segment elevation, often followed by a negative T wave; 2) very closely coupled extrasystoles; and 3) rapid polymorphic VT, which at times may be indistinguishable from VF. The ST segment elevation may also display a saddleback appearance (Miyazaki et al., 1996) and VT in rare cases may be monomorphic. (Shimada et al., 1996)

The ECG sign of the Brugada syndrome is dynamic and often concealed, but can be unmasked by potent sodium channel blockers such as flecainide, ajmaline, procainamide, disopyramide, propafenone and pilsicainide (Brugada et al., 2000c;Shimizu et al., 2000a;Priori et al., 2000a) , although the specificity of this effect for uncovering patients at risk for sudden death was raised as a concern in some studies (Priori et al., 2000b) , but not others. (Gasparini et al., 2003) A consensus report dealing with diagnostic criteria for the Brugada syndrome has recently been published. (Wilde et al., 2002) Sudden unexplained death syndrome (SUDS), a disorder most prevalent in southeast Asia, and Brugada syndrome are phenotypically, genetically and functionally the same disorder. (Vatta et al., 2002) Alings and Wilde reviewed the literature in 1999, and reported that of 163 patients who met the criteria for Brugada Syndrome, 58% were of Asian origin. (Alings & Wilde, 1999)

More recent reports indicate that in addition to sodium channel blockers and a febrile state, vagotonic agents, α adrenergic agonists, β adrenergic blockers, tricyclic antidepressants, first generation antihistaminics (dimenhydrinate), alcohol intoxication, insulin+glucose, and cocaine toxicity can unmask the Brugada syndrome or lead to accentuation of ST segment elevation in patients with the syndrome. (Brugada et al., 2000b;Brugada et al., 2000c;Miyazaki et al., 1996;Babaliaros & Hurst, 2002;Goldgran-Toledano et al., 2002;Tada et al., 2001;Pastor et al., 2001;Ortega-Carnicer et al., 2001;Nogami et al., 2003) These represent acquired form of the Brugada syndrome.

An urgent goal of on-going research is the identification of patients at greatest risk for sudden death. (Brugada et al., 2002;Priori et al., 2002) Patients initially presenting with aborted sudden death are at highest risk for a recurrence (69%), whereas those presenting with syncope and a spontaneously appearing Brugada ECG sign have a recurrence rate of 19%. The study by Brugada et al. (Brugada et al., 2002) found an 8% occurrence of cardiac events in initially asymptomatic patients. Among the asymptomatic patients, highest risk can be assigned to those who display the Brugada sign spontaneously. Patients in whom ST segment elevation appeared only after sodium channel blocker challenge appeared to be at minimal or no risk for arrhythmic events. The study by Brugada et al. also suggested that among asymptomatic patients inducibility of VT during electrophysiologic study (EPS) may be prognostic of risk. Studies by Priori et al, (Priori et al., 2002) Shimizu et al. (Kanda et al., 2002) and Eckardt et al. (Eckardt et al., 2001) failed to find an association between inducibility and recurrence of VT/VF among Brugada patients, although these studies did not differentiate between asymptomatic and symptomatic patients.

2.    Cellular and Ionic Mechanisms

The cellular mechanisms believed to underlie the Brugada syndrome evolved in the early 1990’s on a parallel but separate track from that of the clinical syndrome. All-or-none repolarization of the ventricular epicardial action potential and phase 2 reentry secondary to sodium channel block or ischemia were first reported about a decade ago. (Antzelevitch et al., 1991;Krishnan & Antzelevitch, 1991;Krishnan & Antzelevitch, 1993)

ST segment elevation in the Brugada syndrome has been proposed to be secondary to a rebalancing of the currents active at the end of phase 1, leading to accentuation of the action potential notch in right ventricular epicardium (see (Antzelevitch, 2001) for references). A transient outward current (I_to)-mediated spike and dome morphology, or notch, in ventricular epicardium, but not endocardium, has been shown to create a transmural voltage gradient responsible for the inscription of the electrocardiographic J wave in larger mammals and in man (Yan & Antzelevitch, 1996) . Under normal conditions, the ST segment is isoelectric because of the absence of transmural voltage gradients at the level of the action potential plateau. Accentuation of the right ventricular notch under pathophysiologic conditions leads to exaggeration of transmural voltage gradients and thus to accentuation of the J wave, causing and apparent ST segment elevation. (Antzelevitch, 2001) ) The repolarization waves take on a saddleback or coved appearance depending on the timing of repolarization of epicardium relative to endocardium. A delay in epicardial activation leads to inversion of the T wave. The down-sloping ST segment elevation, or accentuated J wave, observed in the experimental wedge models often appears as an R’, suggesting that the appearance of a RBBB morphology in Brugada patients may be due at least in part to early repolarization of right ventricular (RV) epicardium, rather than to marked impulse delay or conduction block in the right bundle. Indeed RBBB criteria are not fully met in many case of Brugada syndrome (Gussak et al., 1999) .

The arrhythmogenic substrate is thought to arise when a further shift in the balance of current leads to loss of the action potential dome at some epicardial sites but not others. Loss of the action potential dome in epicardium but not endocardium results in the development of a marked transmural dispersion of repolarization and refractoriness, responsible for the development of a vulnerable window. A closely coupled extrasystole can capture this vulnerable period and induce a reentrant arrhythmia. Loss of the action potential dome in epicardium is usually heterogeneous, leading to the development of epicardial dispersion of repolarization. Conduction of the action potential dome from sites at which it is maintained to sites at which it is lost causes local re-excitation via a phase 2 reentry mechanism, leading to the development of the very closely-coupled extrasystole, which triggers a circus movement reentry in the form of VT/VF (Lukas & Antzelevitch, 1996;Yan & Antzelevitch, 1999) . The phase 2 reentrant beat fuses with the negative T wave of the basic response. Because the extrasystole originates in epicardium, the QRS complex is largely comprised of a negative Q wave, which serves to accentuate the inverted T wave, giving the ECG a more symmetrical appearance, morphology commonly observed in the clinic preceding the onset of polymorphic VT. Support for these hypotheses derives from experiments involving the arterially perfused right ventricular wedge preparation (Yan & Antzelevitch, 1999) . Further evidence in support of these mechanisms derives from the recent studies of Kurita et al. in which monophasic action potential (MAP) electrodes where positioned on the epicardial and endocardial surfaces of the right ventricular outflow tract (RVOT) in patients with the Brugada syndrome. (Kurita et al., 2002;Antzelevitch et al., 2002)

3.    Genetic Aspects of the Brugada Syndrome

The Brugada syndrome displays an autosomal dominant mode of transmission. The first gene to be linked to the Brugada syndrome was SCN5A, the gene that encode for the a subunit of the cardiac sodium channel gene. (Chen et al., 1998) Over 50 SCN5A mutations have been linked to the syndrome over the past 5 years. (see (Antzelevitch, 2001;Priori et al., 2002;Balser, 2001) for references) These mutations have been shown to cause either: 1) failure of the sodium channel to express; 2) reduced current due to a shift in the voltage- and time-dependence of sodium channel current (I_Na) activation, inactivation or reactivation; or 3) reduced contribution of I_Na during the early phases of the action potential due to accelerated inactivation of the sodium channel. Premature inactivation of the channel was observed at physiological temperatures, but not at room temperature. (Dumaine et al., 1999) Moreover, because this characteristic of the mutant channel was exaggerated at temperatures above the physiological range, we suggested that the syndrome may be unmasked, and that patients with the Brugada syndrome may be at an increased risk, during a febrile state. (Dumaine et al., 1999) A number of Brugada patients displaying fever-induced polymorphic VT have been identified since this report. (see (Antzelevitch & Brugada, 2002) for references). Another locus on chromosome 3, close to but distinct from SCN5A, was recently linked to the syndrome. (Weiss et al., 2002) Approximately 20% of Brugada cases have been linked to SCN5A mutations. A long list of candidate genes encoding for a variety of ion channels and other proteins have been proposed. (Antzelevitch, 2001;Smits et al., 2002)

4.    Device and Pharmacologic Approach to Therapy

ICD implantation is the only established effective treatment for the Brugada syndrome. (Brugada et al., 2000a;Brugada et al., 1999) This however is not an ideal solution for infants and young children or for adults residing in regions of the world where an ICD is currently unaffordable. The pharmacologic approach to therapy is focused on a rebalancing of currents active in the early phases of the right ventricular epicardial action potential so as to reduce the magnitude of the action potential notch and/or restore the action potential dome. Studies involving the canine right ventricular wedge preparation indicate that agents capable of inhibiting I_to, including quinidine and tedisamil, or agents that boost the calcium current, such as isoproterenol, may be useful. (Antzelevitch, 2001;Yan & Antzelevitch, 1999) Both have been shown to be effective in normalizing ST segment elevation in patients with the Brugada syndrome and in controlling electrical storms, particularly in children, (Alings et al., 2001;Shimizu et al., 2000b;Tanaka et al., 2001) but other than the study by Belhassen and co-workers involving quinidine, none have as yet demonstrated long term efficacy in the prevention of sudden death. (Belhassen et al., 1999;Belhassen et al., 2002) A recent report demonstrated the ability of a phospodiesterase III inhibitor, cilostazol, (Tsuchiya et al., 2002) to normalize the ST segment, most likely by reducing by augmenting calcium channel current (I_Ca) and accelerating heart rate.

Acknowledgments

Supported by grants from the National Institutes of Health (HL 47678), the American Heart Association, NYS Affiliate and the Masons of NYS and Florida.

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