Brugada syndrome_ clinical_ genetic_ molecular_ cellular and ionic aspects_

Antzelevitch178Expert Rev. Cardiovasc. Ther 1(2), (2003)Electron beam computed tomography has uncovered wall motion abnormalities in a majority of Brugada patients tested [12]. Although such contractile abnormalities are commonly con-sidered pathognomonic of structural disease, recent studies sug-gest that such contractile dysfunction can result from loss of the action potential dome in regions of right ventricular (RV) epi-cardium, unrelated to any type of morphological defect [13,14].Loss of the dome leads to contractile dysfunction because cal-cium entry into the cells is greatly diminished and sarcoplasmic reticulum calcium stores are depleted.Signal-averaged ECG (SAECG) recordings have demon-strated late potentials in patients with the Brugada syndrome,especially in the anterior wall of the RV outflow tract (RVOT)[15,16]. Nagase and coworkers recorded delayed potentials from the epicardial surface of the anterior wall of the RVOT , which coincided with late potentials in the SAECG, in patients with the Brugada syndrome [17]. Although late potentials are gener-ally regarded as being representative of delayed activation of the myocardium secondary to structural defects, recent studies sug-gest that in the case of the Brugada syndrome these late and delayed potentials may represent the delayed second upstroke of the epicardial action potential or local Phase 2 re-entry. [14]Diagnostic criteriaST segment elevation is associated with a wide variety of benign as well as malignant pathophysiologic conditions. A differential diagnosis is at times difficult, particularly when the degree of ST segment elevation is relatively small and the specificity of sodium channel blockers, such as flecainide,ajmaline, procainamide, disopyramide, propafenone and pil-sicainide to identify patients at risk is uncertain [18–20]. A con-sensus report recently published by the Arrhythmia Working Group of the European Society of Cardiology addresses these and other ambiguities concerning the diagnostic criteria for Brugada syndrome [11,21].Three types of repolarization patterns can be discerned (TABLE 1). Type 1 is characterized by a coved ST segment eleva-tion of 2mm or greater (0.2mV) followed by a negative Twave. Type 2 has a saddleback appearance with a high take-off ST-segment elevation of 2mm or more followed by a trough displaying 1mm or higher ST elevation followed by a positive T wave. Type 3 has either a saddleback or coved appearance with an ST segment elevation of less than 1mm.These patterns may be observed sequentially in the same patient or following the introduction of specific drugs.Brugada syndrome is definitively diagnosed when Type 1 ST segment elevation is observed in more than one lead (V 1–V 3),in the presence or absence of a sodium channel blocker, in con-junction with one of the following: documented ventricular fibrillation, self-terminating polymorphic ventricular tachycar-dia, a family history of sudden cardiac death (<45years), coved Type ECGs in family members, inducibility of VT with pro-grammed electrical stimulation, syncope or nocturnal agonal respiration. Confounding factors that could account for the ECG abnormality should be excluded.The diagnosis is also considered positive when a Type 2 (sad-dleback) or Type 3 ST segment elevation is observed in more than one right precordial lead under baseline conditions and conversion to Type 1 occurs following challenge with a sodium channel blocker (ST segment elevation ≥2mm). One or more of the clinical criteria described above should also be present.Drug-induced conversion of Type 3 to Type 2 ST segment elevation is considered inconclusive.Clinical characteristicsObservations from Japan suggest that in some cases arrhythmia initiation is bradycardia-related [22]. This may contribute to the higher incidence of sudden death at night in individuals with the syndrome and may account for the success of pacing in control-ling the arrhythmia in isolated cases of the syndrome [23]. How-ever, not all the patients die at night and not all the cases are con-trolled with rapid ventricular pacing. South Asian patients who have the ECG pattern usually develop VT/ventricular fibrilla-tion (VF) during sleep at night. Implantable cardioverter–defi-brillator (ICD) interrogation in these patients has failed to show clear evidence of bradycardia-dependence of VT/VF .VT/VF often terminates spontaneously in patients with the Brugada syndrome, as first reported by Bjerregaard and colleagues [24]. Many such self-terminating episodes have since been observed with ICD interrogation. This may explain why patients present with syncope or wake up at night after episodes of agonal respiration caused by the arrhythmia. Our understanding of why some episodes self-terminate and others sustain, leading to sudden death, is incomplete. The influence of drugs, electrolyte levels,sleep apnea and autonomic factors remains largely unknown.The syndrome manifests primarily during adulthood, with a mean age of sudden death of approximately 40years. The youngest patient diagnosed with the syndrome was 2weeks old, whereas the oldest was 84 [25]. The syndrome is believed to be responsible for 4–12% of all sudden deaths and approxi-mately 20% of deaths in patients with structurally normal hearts. The incidence of the disease is on the order of 5 per 10,000 inhabitants and, apart from accidents, is the leading cause of death of men under the age of 40 in regions of the world where the syndrome is endemic. Since the ECG is so dynamic and often concealed, it is difficult to estimate the true incidence of the disease in the general population [26].Table 1. Diagnostic criteria for Brugada syndrome.ST segment abnormalities in leads V 1–V 3.Type 1Type 2Type 3J point ≥ 2 mm ≥ 2 mm ≥ 2 mm T waveNegative Positive or biphasic Positive ST–T configuration Coved type Saddleback Saddleback ST segment (terminal portion)Gradually descendingElevated ≥ 1 mmElevated < 1 mmBrugada syndrome 179The electrocardiographic manifestations of the Brugada syn-drome are often concealed but can be unmasked by sodium channel blockers, a febrile state, vagotonic agents, α-adrenergic agonists, β-adrenergic blockers, tricyclic antidepressants, first-generation antihistamines (e.g., dimenhydrinate), a combina-tion of glucose and insulin, hypokalemia and by alcohol and cocaine toxicity [4,18,27–34].Local pressure applied to the RV wall as in the case of a medi-astinal tumor has also been reported to induce an ECG pattern similar to the Brugada syndrome [35]. This ECG pattern disap-pears after tumor removal, suggesting that it is caused by com-pression of the RV outflow tract [35]. Another case of pericardial fluid compressing the right ventricle with Brugada-like ECG pat-tern was reported in a patient with rheumatoid arthritis [36]. The ECG normalized after surgery to correct the hemopericardium.Identification of patients at riskRisk stratification aimed at the identification of patients at risk for sudden death is the essential goal of research teams world-wide [37,38]. The study by Brugada and colleagues found that 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% [37]. An 8% occurrence of cardiac events was observed in initially asymptomatic patients.Among asymptomatic patients, those at highest risk displayed the Brugada sign spontaneously; those in whom ST segment elevation appeared only after provocation with sodium channel blockers appear to be at minimal or no risk for arrhythmic events. Brugada patients at the highest risk are males with inducible VT/VF and a spontaneously elevated ST segment.Recent studies have suggested that combined electrocardio-graphic markers may be helpful in risk stratification. Atarashi and colleauges [39] used the width of the S wave and the ST segment elevation magnitude, whereas Morita and col-leagues [40] combined ST segment elevation and the presence of late potentials.Brugada and coworkers suggested that among asymptomatic patients, inducibility of VT during electrophysiologic study (EPS) may forecast risk [37]. Studies by Priori and coworkers [38],Kanda and coworkers [41] and Eckardt and coworkers [42], how-ever, failed to find an association between inducibility and recur-rence of VT/VF among Brugada patients (both asymptomatic and symptomatic). These discrepancies may be due to differ-ences in the inclusion of asymptomatic patients and the use of multiple testing centers with nonstandardized stimulation protocols. Additional studies are needed to further define the therapeutic approach for asymptomatic patients. Meanwhile,the current recommendation is that symptomatic patients with the Brugada pattern (aborted sudden cardiac deaths or syncope)should receive an ICD regardless of EPS findings. The recom-mendation by Brugada and colleagues is for asymptomatic patients to undergo EPS and, if inducible, have an ICD implanted. As additional data become available, the role of EPS in risk stratification will no doubt be further refined.Genetic factors underlying the Brugada syndromeInheritance of the Brugada syndrome is via an autosomal dom-inant mode of transmission. The first and only gene to be linked to the Brugada syndrome is SCN5A , the gene coding for the α subunit of the cardiac sodium channel gene [43]. Nearly five dozen mutations in SCN5A have been linked to the syn-drome over the past 4years (see [38,44–46] for references).Approximately two dozen of the these mutations have been studied in expression systems and shown to result in loss of function due to one or more of the following: •Failure of the sodium channel to express•A shift in the voltage- and time-dependence of I Na activation,inactivation or reactivation•Entry of the sodium channel into an intermediate state of inactivation from which it recovers more slowly •Accelerated inactivation of the sodium channelThe premature inactivation of the sodium channel is observed at physiological temperatures but not at room temper-ature [47]. Since 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 [47]. A number of Brugada patients dis-playing fever-induced polymorphic VT have been identified since the publication of this report (see [48] for references).Another locus on chromosome 3, close to but distinct from SCN5A , has recently been linked to the syndrome in a large pedigree in which the syndrome is associated with progressive conduction disease, a low sensitivity to procainamide and a relatively good prognosis [49].Cellular & ionic mechanismsPhase 2 re-entry and other characteristics of strong sodium channel blockade, which give rise to a Brugada-like syndrome,were described in the early 1990s and evolved in parallel with the clinical syndrome [50–53]. Studies conducted over the past decade suggest that rebalancing of the currents active at the end of Phase 1, leading to an accentuation of the action potential notch in RV epicardium, is responsible for the accentuated J wave or ST segment elevation associated with the Brugada syn-drome (see [44] for references). In larger mammals, the presence of a transient outward current (I to )-mediated spike and dome morphology, or notch, in ventricular epicardium but not endo-cardium, creates a transmural voltage gradient responsible for the inscription of the electrocardiographic J wave (FIGURE 1A)[2,54]. The ST segment is isoelectric due to the absence of trans-mural voltage gradients at the level of the action potential pla-teau. Accentuation of the RV action potential notch under pathophysiologic conditions leads to exaggeration of transmu-ral voltage gradients and thus to accentuation of the J wave or to J point elevation. If the epicardial action potential continues to repolarize before that of the endocardium, the T wave will remain positive, giving rise to a saddleback configuration of the ST segment elevation. Further accentuation of the notch mayAntzelevitch180Expert Rev. Cardiovasc. Ther 1(2), (2003)be accompanied by a prolongation of the epicardial action potential such that the direction of repolarization across the RV wall and transmural voltage gradients are reversed, leading to the development of a coved-type ST segment elevation and inversion of the T wave, typically observed in the ECG of Bru-gada patients (FIGURE 1B). A delay in epicardial activation may also contribute 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 right bundle branch block (RBBB)morphology in Brugada patients may be due at least in part to early repolarization of RV epicardium, rather to impulse con-duction block in the right bundle. Indeed, a rigorous applica-tion of RBBB criteria reveals that a large majority of RBBB-like morphologies encountered in cases of Brugada syndrome do not fit the criteria for RBBB [55]. Also noteworthy is that attempts by Miyazaki and coworkers to record delayed activation of the RV in Brugada patients met with failure [4].Despite the appearance of a typical Brugada sign, the electro-physiological changes shown in FIGURE 1B do not give rise to an arrhythmogenic substrate. We believe that the arrhythmogenic substrate develops with a further shift in the balance of current leading to loss of the action potential dome at some epicardial sites but not others (FIGURE 1C). Loss of the action potential dome in the epicardium but not endocardium results in the development of a marked transmural dispersion of repolariza-tion and refractoriness, responsible for the development of a vulnerable window, which can be captured by a premature impulse or extrasystole to trigger a re-entrant arrhythmia. Loss of the action potential dome in epicardium is usually heteroge-neous, 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 Phase 2 re-entry (FIGURE 1D), leading to the development of a very closely coupled extra systole, which captures the vulnerable window across the wall, thus triggering a circus movement re-entry in the form of VT/VF [56,57]. The Phase 2 re-entrant beat fuses with the negative T wave of the basic response. Since the extra systole originates in the epicar-dium, the QRS complex is largely comprised of a negative Q wave, which serves to accentuate the negative deflection of the inverted T wave, giving the ECG a symmetrical appearance,often observed in the clinic preceding the onset of polymorphic VT . Support for these hypotheses derives from experimentsA. NormalB. Brugada syndrome (coved)T ransmural voltage gradientTransmural voltage gradient Endo EpiEndo EpiEndo EpiEndo EpiM Epi (Phase 2 re-entry)C. Brugada sundrome(heterogeneous loss of AP dome)D. Brugada syndrome (Phase 2 re-entry)T ransmembrane action potentialsECG (V 2)ECG (V 2)Transmembrane action potentials-100mV200 msTransmural dispresion of repolarization Epicardial dispersion of repolarizationFigure 1. Schematic representation of right ventricular epicardial action potential changes thought to underlie the electrocardiographic manifestation of the Brugada syndrome. Modified from [54], with permission.Brugada syndrome181involving the arterially perfused RV wedge preparation [57] and from recent studies in which MAP electrodes were positioned on the epicardial and endocardial surfaces of the RVOT in patients with the Brugada syndrome [53,58].The ability of local pressure to give rise to an ST segment ele-vation has been demonstrated experimentally in the arterially perfused RV wedge preparation [59]. Focal pressure was shown to cause loss of the action potential dome at some right epicar-dial sites but not others. The potential for this mechanism to give rise to closely coupled Phase 2 re-entrant extra systoles and VT was also demonstrated in this experimental study.An interesting aspect of the Brugada syndrome is that despite equal genetic transmission of the disease, the clinical phenotype is 8 to 10 times more prevalent in males than in females. The basis for this sex-related distinction was recently shown to be due to a more prominent I to -mediated action potential notch in the RV epicardium of males versus females [60]. The more prominent I to causes the end of Phase 1 of the RV epicardial action potential to repolarize to more negative potentials in tis-sue and arterially perfused wedge preparations from males,facilitating loss of the action potential dome and the develop-ment of Phase 2 re-entry and polymorphic VT .Box 1. Device and pharmacologic considerations for therapy in the Brugada syndrome.Devices!ICD: only established effective therapy ?PacemakerPharmacologicX Amiodarone: does not protect [63]X β-blockers: does not protect [63]!β-adrenergic agonists: isoproterenol [4,67]!Phosphodiesterase inhibitors: cilostazol [71]X Class IC antiarrhythmics:flecainide, propafenone: contraindicated Class IA antiarrhythmicsX Procainamide, disopyramide: contraindicated !Quinidine [57,65,66,70]?Tedisamil!I to Blockers: cardioselective and ion channel-specificA. PinacidilB. +4-APEpi 1Epi 2ECG500 ms 300 ms50 mV50 mV50 mVFigure 2. ECG and arrhythmias with typical features of the Brugada Syndrome recorded from a canine right ventricular wedge preparation. (A) Polymorphic VT/VF induced by the potassium channel opener pinacidil (10 µM). Action potentials from two epicardial sites (Epi 1 and Epi 2) and a transmural ECG were simultaneously recorded. Loss of the dome at Epi 1 but not Epi 2 creates a marked dispersion of repolarization, giving rise to a Phase 2 re-entrant extrasystole. The extrasystolic beat then triggers an episode of ventricular tachycardia/fibrillation. (B) I to block using 4-AP (2 mM) restores the action potential dome at Epi 1, thus reducing dispersion of repolarization and suppressing all arrhythmic activity. BCL = 2000 ms. Modified from [57]with permission.4-AP: 4-aminopyridine; ECG: Electrocardiogram; VF: Venous thromboembolism; VT: Ventricular tachycardia.Antzelevitch182Expert Rev. Cardiovasc. Ther 1(2), (2003)A rebalancing of currents active at the end of Phase 1 under-lies the unmasking of the syndrome in response to drugs. Vago-tonic agents, potassium–ATP current (I K–ATP ) activators and hypokalemia achieve this by augmenting outward currents,whereas sodium channel blockers, β-blockers, cocaine, antide-pressants and antihistamines such as terfenadine are thought to accomplish this by reducing inward currents.Expert opinion & five-year viewDespite the important strides in the identification and charac-terization of the Brugada syndrome over the past decade,progress relative to therapy has been less impressive. The various device and pharmacologic therapies tested clinically or suggested based on experimental evidence are listed in BOX 1. ICD implantation is the only proven effective treat-ment for the disease [61,62]. This however is not an adequate solution for infants and young children or for adults resid-ing in regions of the world where an ICD is unaffordable.Although arrhythmias and sudden death generally occur during sleep or at rest and have been associated with brady-cardic states, a potential therapeutic role for pacing remains largely unexplored.Control Procainamide QuinidineFigure 3. Twelve-lead ECG tracings in an asymptomatic 26-year-old man with a Brugada sign. (A) during control: a ‘saddle-type’ ST-segment elevation is observed in V 2; (B) after intravenous administration of 750mg procainamide, the ‘saddle-type’ ST-segment elevation changed into a ‘coved-type’; and a few days after oral administration of quinidine bisulfate (1500mg/day, serum quinidine level 2.6mg/l), marked attenuation of the ST-segment elevation is noted in right precordial leads. Note that ventricular fibrillation could be induced with double ventricular extrastimulation both during control and procainamide infusion. In contrast, only a few repetitive ventricular complexes could be induced during quinidine therapy using an aggressive protocol using quadruple ventricular extrastimulation. This patient remained asymptomatic during quinidine therapy during a 12-month follow-up. From [65] with permission.ECG: Electrocardiogram.Brugada syndrome 183The pharmacologic approach to therapy has been tailored to a rebalancing of currents active during the early phases of the epicardial action potential in the right ventricle so as to reduce the magnitude of the action potential notch and/or restore the action potential dome. Antiarrhythmic agents, such as amio-darone and β-blockers, have been shown to be ineffective [63].Class IC antiarrhythmic drugs, such as flecainide and propaf-enone are clearly contraindicated for reasons previously dis-cussed. Class IA agents, such as procainamide and disopyra-mide, are contraindicated for similar reasons. Other Class IA agents, such as quinidine and tedisamil, however, may exert a therapeutic action. Since the presence of a prominent I to is at the heart of the mechanism underlying the Brugada syndrome,any agent that inhibits this current may be protective (FIGURE 2). Cardioselective and I to -specific blockers are not cur-rently available. The only agent on the market in the USA with significant I to -blocking properties is quinidine. It is for this rea-son that we suggested several years ago that this agent may be of therapeutic value in the Brugada syndrome [64]. Experimen-tal studies have since shown quinidine to be effective in restor-ing the epicardial action potential dome, thus normalizing the ST segment and preventing Phase 2 re-entry and polymorphic VT in experimental models of the Brugada syndrome [57].Clinical evidence of the effectiveness of quinidine in normaliz-ing ST segment elevation in patients with the Brugada syn-drome has been reported (FIGURE 3) [65,66], although clinical tri-als designed to assess the efficacy of this agent are not available.Agents that boost the calcium current, such as isoproterenol,may be useful as well [44,57]. Both types of agents have been shown to be effective in normalizing ST segment elevation in patients with the Brugada syndrome and in controlling electri-cal storms, particularly in children [65–69]. Other than the study by Belhassen and coworkers involving quinidine, none have as yet demonstrated long-term efficacy in the prevention of sudden death [65,70]. The most recent addition to the phar-macological armamentarium is the phospodiesterase III inhib-itor, cilostazol [71], which normalizes the ST segment most likely by augmenting calcium current (I Ca ) as well as by reduc-ing I to secondary to an increase in heart rate. Finally, an exper-imental antiarrhythmic agent, tedisamil, with potent actions to block I to , among other outward currents, has been suggested as a therapeutic candidate [44]. Tedisamil may be more potent than quinidine because it lacks the relatively strong inwardcurrent-blocking actions of quinidine. The development of a cardioselective and I to -specific blocker would be a most wel-come addition to the limited therapeutic armamentarium cur-rently available to combat this disease. One potential candi-date is an agent recently reported to be a selective I to and I Kur blocker, AVE0118. Appropriate clinical trials are needed to establish the effectiveness of all of the above pharmacologic agents as well as the possible role of pacemakers.AcknowledgementSupported by grants from the National Institutes of Health (HL 47678), the American Heart Association, New York State Affiliate and the Masons of New York State and Florida.Key issues•Brugada syndrome, the second leading cause of death of young men in southeast Asia, commonly presents in the third or fourth decade of life, although it has been diagnosed in infants as young as 2 weeks and an individual as old as 84.•Although ST segment elevation and polymorphic ventricular tachycardia (VT), characteristic of the Brugada syndrome, may be seen in a small segment of the arrhythmogenic right ventricular cardiomyopathy/dysplasia patientpopulation, the two syndromes are generally distinct with respect to clinical presentation, response to drugs, and genetic predisposition or cause. Most Brugada patients have structurally normal hearts.•Available data point to accentuation of the right ventricular action potential notch and eventual loss of the actionpotential dome as the basis of ST segment elevation and the development of the substrate VT/ventricular fibrillation.•As the presence of a prominent transient outward current (I to ) is at the heart of the syndrome, cardioselective and ion channel-specific block of I to is considered to be the ideal approach to pharmacologic therapy.•Although implantable cardioverter–defibrillatorimplantation is the only proven approach to preventing sudden death, the role of pacemakers, particularly in the subset of patients in whom VT is bradycardia-dependent, remains to be established.ReferencesPapers of special note have been highlighted as:• of interest•• of considerable interest1Brugada P , Brugada J. 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