Brugada Syndrome



 Since its introduction as a new clinical entity by Pedro and Josep Brugada in 1992, the Brugada syndrome has attracted great interest because of its high incidence in many parts of the world and its association with high risk of sudden death, especially in males as they enter their third and fourth decades of life. Recent years have witnessed a dramatic rise in the number of reported cases and a great proliferation of papers serving to define the clinical, genetic, cellular, ionic, and molecular aspects of the disease. A consensus conference report published in 2002 delineated diagnostic criteria for the syndrome. A second consensus conference report published in 2005 focused on risk stratification schemes and approaches to therapy.

Diagnostic Criteria

Characterized by an ST-segment elevation in the right precordial electrocardiogram (ECG) leads and a high incidence of sudden death in patients with structurally normal hearts, the Brugada syndrome generally manifests during adulthood. The average age at the time of initial diagnosis or sudden death is 40 ± 22. The youngest patient diagnosed with the syndrome is 2 days of age, and the oldest is 84 years.

3 tipi brugada

Because the ECG is so dynamic and often concealed, it is difficult to estimate the true prevalence of the disease in the general population. The prevalence of the Brugada syndrome is estimated at 1–5 per 10,000 inhabitants worldwide. The frequency is lower in western countries and higher (≥5 per 10,000) in Southeast Asia, especially in Thailand and the Philippines where Brugada syndrome is considered to be the major cause of sudden death in young individuals. In these countries, the syndrome is often referred to as sudden unexplained nocturnal death syndrome (SUNDS).

The electrocardiographic manifestations of the Brugada syndrome when concealed can be unmasked by sodium channel blockers, a febrile state, or vagotonic agents. Three types of repolarization patterns in the right precordial leads are recognized.Type 1 ST-segment elevation is diagnostic of Brugada syndrome and is characterized by a coved ST-segment elevation ≥2 mm (0.2 mV) followed by a negative T wave. Type 2 ST-segment elevation has a saddleback appearance with a high take-off ST-segment elevation of ≥2 mm followed by a trough displaying ≥1 mm ST elevation followed by either a positive or biphasic T wave. Type 3 ST-segment elevation has either a saddleback or coved appearance with an ST-segment elevation of <1 mm. These three patterns may be observed sequentially in the same patient or following the introduction of specific drugs. Type 2 and 3 ST-segment elevation should not be considered diagnostic of the Brugada syndrome. A Brugada ECG refers to the manifestation of a Type 1 ST-segment elevation. Brugada syndrome is definitively diagnosed when a Type 1 ST-segment elevation (Brugada ECG) is observed in more than one right precordial lead (V1-V3), in the presence or absence of sodium channel blocking agent, and in conjunction with one or more of the following: documented VF, polymorphic ventricular tachycardia (VT); a family history of SCD (<45 years old); coved-type ECGs in family members; inducibility of VT with programmed electrical stimulation (PES); syncope; or nocturnal agonal respiration.

 diagnostic criteria

Differential diagnosis of the Brugada syndrome must be approached with care since ST-segment elevation is associated with a wide variety of benign as well as malignant pathophysiologic conditions. Definitive diagnosis is difficult when the degree of basal ST-segment elevation is relatively small and the specificity of sodium channel blockers, such as flecainide, ajmaline, procainamide, disopyramide, propafenone, and pilsicainide to identify patients at risk is uncertain.

The sodium challenge should be monitored with a continuous ECG recording (speed 10 mm/s and interposed 50 mm/) and should be terminated when (1) the diagnostic Type 1 ST-segment elevation, or Brugada ECG, develops; (2) ST segment in Type 2 increases by ≥2 mm; (3) premature ventricular beats or other arrhythmias develop; or (4) QRS widens to ≥130% of baseline. Sodium channel blockers should be used with particular caution in the presence of atrial and/or ventricular conduction disease (presence of wide QRS, wide P waves, or prolonged PR intervals). Isolated cases of mechano-electrical dissociation have been reported. Isoproterenol and sodium lactate may be effective antidotes.

Confounding factor(s) that could account for the ECG abnormality need to be carefully excluded. Exaggerated ST-segment elevation is sometimes observed for a brief period following DC cardioversion, and this must be factored in when first evaluating a patient following defibrillation.

Another important confounding factor is the ST-elevation encountered in well-trained athletes. The ST-segment elevation encountered in athletes can be distinguished by virtue of the fact that it is up-sloping rather than downsloping and is largely unaffected by challenge with a sodium channel blocker. In addition, a variety of drugs have been reported to produce a Brugada-like ST-segment elevation .Myocarditis and some forms of arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) can lead to a Brugada-like phenotype (see below). The extent to which these acquired forms of Brugada syndromes have a genetic predisposition is the subject of intense investigation.

Diagnosis of Brugada syndrome is also considered positive when a Type 2 (saddleback pattern) or Type 3 ST-segment elevation is observed in more than one right precordial lead under baseline conditions and can be converted to the diagnostic Type 1 pattern occurs upon exposure to sodium channel blocker (ST-segment elevation should be ≥2 mm). 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 for diagnosis of Brugada syndrome.

Placement of the right precordial leads in a superior position (up to the 2nd intercostal spaces above normal) can increase the sensitivity of the ECG for detecting the Brugada phenotype in some patients, both in the presence or absence of a drug challenge.

ECG brugada

A slight prolongation of the QT interval is sometimes observed associated with the ST-segment elevation. The QT interval is prolonged more in the right versus left precordial leads, presumably due to a preferential prolongation of action potential duration (APD) in right ventricular (RV) epicardium secondary to accentuation of the action potential (AP) notch.A corrected QT (QTc) >460 ms in V2 has been shown to be associated with arrhythmic risk. Depolarization abnormalities including prolongation of P-wave duration, PR and QRS intervals are frequently observed, particularly in patients linked to SCN5A mutations. PR prolongation likely reflects HV conduction delay.

More recent reports indicate that approximately 20% of Brugada syndrome patients develop supraventricular arrhythmias. It is as yet unknown whether atrial vulnerability is correlated with ventricular inducibility of arrhythmias or whether atrial arrhythmias may serve as triggering events for VT/VF, although the latter seems unlikely based on current knowledge. Slowed atrial conduction as well as atrial standstill have been reported in association with the syndrome.

In many cases, arrhythmia initiation is bradycardia-related. 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 controlling the arrhythmia in isolated cases of the syndrome. However, not all patients die at night and not all the cases are controlled with rapid ventricular pacing. South Asian patients who have the ECG pattern usually develop VT/VF during sleep at night. Makiyama and co-workers reported that loss-of-function SCN5A mutations resulting in Brugada syndrome are distinguished by profound bradyarrhythmias. Pertinent to this observation is the recent report by Scornik and co-workersdemonstrating expression of the cardiac sodium channel gene, SCN5A, in intracardiac ganglia. This interesting finding suggests that loss-of-function mutations in SCN5A may not only create the substrate for reentry in ventricular myocardium, but may also increase vagal activity in intracardiac ganglia, thus facilitating the development of arrhythmias in patients with the Brugada syndrome.

A polymorphic VT resembling a rapid Torsade de Pointes (TdP) arrhythmia is most commonly associated with the Brugada syndrome. Monomorphic VT is observed infrequently and is generally more prevalent in children and infants.VT/VF often terminates spontaneously in patients with the Brugada syndrome, as first reported by Bjerregaard et al. This may explain why patients wake up at night after episodes of agonal respiration caused by the arrhythmia.

SUNDS, also known as SUDS, a disorder most prevalent in Southeast Asia, and Brugada syndrome have recently been shown to be phenotypically, genetically, and functionally the same disorder. Sudden and unexpected death of young adults during sleep, known in the Philippines as bangungut (“to rise and moan in sleep”), was first described in the Philippine medical literature in 1917. In Japan, this syndrome, known as pokkuri (“sudden and unexpectedly ceased phenomena”), was reported as early as 1959. In 1997, Nademanee et al. reported that among 27 Thai men referred for aborted cases of what was known in Thailand as Lai Tai (“death during sleep”), as many as 16 had the ECG pattern of Brugada Syndrome. In their review of the literature in 1999, Alings and Wilde found that of the 163 patients who met the criteria for Brugada Syndrome, 58% were of Asian origin.

Genetic Factors Underlying the Brugada Syndrome

Brugada syndrome is inherited via an autosomal dominant mode of transmission. The first gene to be linked to the Brugada syndrome is SCN5A, the gene encoding for the α-subunit of the cardiac sodium channel gene. highlights the diversity of SCN5A mutations associated with the Brugada syndrome. Of note, mutations in SCN5A are also responsible for the LQT3 form of the long-QT syndrome and cardiac conduction disease. A number of mutations have been reported to cause overlapping syndromes; in some cases, all three phenotypes are present.




 Over one hundred mutations in SCN5A have been linked to the syndrome in recent years .Only a fraction of these mutations have been studied in expression systems and shown to result in loss of function due either to: (1) failure of the sodium channel to express; (2) a shift in the voltage- and time-dependence of sodium channel current (INa) activation, inactivation, or reactivation; (3) entry of the sodium channel into an intermediate state of inactivation from which it recovers more slowly; or (4) accelerated inactivation of the sodium channel. In in vitro expression systems, the premature inactivation of the sodium channel is sometimes observed at physiological temperatures, but not at room temperature. Acceleration of INa inactivation was still more accentuated at higher than physiological temperatures, suggesting that the syndrome may be unmasked, and that patients with the Brugada syndrome may be at an increased risk, during a febrile state. A number of Brugada patients displaying fever-induced polymorphic VT have been identified since the publication of this report.

Mutations in the SCN5A gene account for approximately 18–30% of Brugada syndrome cases. A higher incidence of SCN5A mutations has been reported in familial than in sporadic cases.

Bezzina and co-workers recently provided interesting evidence in support of the hypothesis that an SCN5A promoter polymorphism common in Asians modulates variability in cardiac conduction, and may contribute to the high prevalence of Brugada syndrome in the Asian population.

A second locus on chromosome 3, close to but distinct from SCN5A, has 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. The gene was recently identified as the Glycerol-3-Phosphate Dehydrogenase 1-Like Gene (GPD1L). A mutation in GPD1L has been shown to result in a partial reduction of INa                     

Knowledge thus far gained through genetic analysis suggests that identification of specific mutations may not be very helpful in formulating a diagnosis or providing a prognosis. There are no clear hotspots and mutations have been reported throughout the SCN5A gene. It is not clear whether some mutations are associated with a greater risk of arrhythmic events or sudden death. Genetic testing is recommended for support of the clinical diagnosis, for early detection of relatives at potential risk, and particularly for the purpose of advancing research and consequently our understanding of genotype-phenotype relations.

Cellular and Ionic Mechanisms Underlying the Development of the Brugada Phenotype

The concept of phase 2 reentry, which is a known trigger for the Brugada syndrome, was described in the early 1990s and evolved in parallel with the clinical discovery of the Brugada syndrome. 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 AP notch in RV epicardium is responsible for the accentuated J wave or ST-segment elevation associated with the Brugada syndrome. Under normal conditions, the appearance of the epicardial AP notch is due principally to the interaction of two ion channel currents. The transient outward current (Ito), which activates during phase 0, contributes most prominently to phase 1 of the AP, whereas the calcium inward current is largely responsible for the second upstroke, giving rise to the AP dome.




Amplification of epicardial and TDR secondary to the presence of genetic defects, pathophysiologic factors, and pharmacologic influences, leads to accentuation of the J wave and eventually to loss of the AP dome, giving rise to extrasystolic activity in the form of phase 2 reentry. Activation of Ito leads to a paradoxical prolongation of APD in canine ventricular tissues, but to abbreviation of ventricular APD in species that normally exhibit brief APs (e.g., mouse and rat). Pathophysiologic conditions (e.g., ischemia, metabolic inhibition) and some pharmacologic interventions (e.g., INa or ICa blockers or IK–ATP, Ito, Ikr, or Iks activators) can lead to marked abbreviation of the AP in canine and feline ventricular cells where Ito is prominent. Under these conditions, canine ventricular epicardium exhibits an all-or-none repolarization as a result of the shift in the balance of currents flowing at the end of phase 1 of the AP. When phase 1 reaches approximately −30 mV, all-or-none repolarization of the AP ensues, leading to loss of the dome as the outward currents overwhelm the inward currents. Loss of the AP dome generally occurs at some epicardial sites but not others, resulting in the development of a marked dispersion of repolarization within the epicardium as well as transmurally, between epicardium and endocardium. Propagation of the AP dome from the epicardial site at which it is maintained to sites at which it is abolished can cause local re-excitation of the preparation. This mechanism, termed phase 2 reentry, produces extrasystolic beats capable of initiating circus movement reentry  . Phase 2 reentry has been shown to occur when RV epicardium is exposed to: (1) K+ channel openers such as pinacidil; (2) sodium channel blockers such as flecainide; (3) increased [Ca2+]o; (4) calcium channel blockers such as verapamil; (5) metabolic inhibition; and (6) simulated ischemia.

Exaggerated or otherwise abnormal J waves have long been linked to idiopathic VF and the Brugada syndrome. The Brugada syndrome is characterized by exaggerated J wave that manifests as an ST-segment elevation in the right precordial leads.1 A number of studies have highlighted the similarities between the conditions that predispose to phase 2 reentry and those that attend the appearance of the Brugada syndrome. Loss of the AP dome in epicardium, but not endocardium, generates a transmural current that manifests on the ECG as an ST-segment elevation, similar to that encountered in patients with the Brugada syndrome. Evidence in support of a phase 2 reentrant mechanism in humans was recently provided by Thomsen et al. and Antzelevitch.

Autonomic neurotransmitters like acetylcholine facilitate loss of the AP dome by suppressing Ica and/or augmenting potassium current. β-adrenergic agonists restore the dome by augmenting ICa. Sodium channel blockers also facilitate loss of the canine RV AP dome via a negative shift in the voltage at which phase 1 begins. These findings are consistent with accentuation of ST-segment elevation in patients with the Brugada syndrome following vagal maneuvers or Class I antiarrhythmic agents, as well as normalization of the ST-segment elevation following β-adrenergic agents and phosphodiesterase III inhibitors. Loss of the AP dome is much more readily induced in right versus left canine ventricular epicardium because of the more prominent Ito-mediated phase 1 in APs in this region of the heart. This distinction is believed to be the basis for why the Brugada syndrome is a RV disease.

Thus, accentuation of the RV epicardial AP notch underlies the ST-segment elevation. Eventual loss of the dome of the RV epicardial AP further exaggerates ST-segment elevation. The vulnerable window created within the epicardium, as well as transmurally, serves as the substrate and phase 2 reentry provides the extrasystole that serves as the trigger which precipitates episodes of VT and VF in the Brugada syndrome. Evidence in support of this hypothesis was recently provided in an arterially perfused canine RV experimental model of the Brugada syndrome The VT and VF generated in these preparations is usually polymorphic, resembling a rapid form of TdP. This activity may be mechanistically related to the migrating spiral wave shown to generate a pattern resembling TdP associated with a normal or long-QT interval.






Much of the focus in the past has been on the ability of a reduction in sodium channel current to unmask the Brugada syndrome and create an arrhythmogenic substrate. A recent report shows that a combination of INa and ICa block is more effective than INa inhibition alone in precipitating the Brugada syndrome in the arterially perfused wedge preparation. High concentrations of terfenadine (5 μM) produce a potent block of INa and ICa, leading to accentuation of the epicardial AP notch following acceleration of the rate from a basic cycle length of 800 to 400 ms. The dramatic accentuation of the notch was due to the effect of the drug to depress phase 0, augment the magnitude of phase 1, and delay the appearance of the second upstroke. With continued rapid pacing, phase 1 becomes more accentuated, until all-or-none repolarization occurs at the end of phase 1 at some epicardial sites but not others, leading to the development of both epicardial dispersion of repolarization (EDR) and TDR .Propagation of the dome from the region where it is maintained to the region at which it is lost results in the development of local phase 2 reentry shows the ability of terfenadine-induced phase 2 reentry to generate an extrasystole, couplet, and polymorphic VT/VF illustrates an example of PES to initiate VT/VF under similar conditions.




Under physiological conditions, the ST segment is isoelectric because of the absence of transmural voltage gradients at the level of the AP plateau .Accentuation of the RV notch under pathophysiologic conditions leads to exaggeration of transmural voltage gradients and thus to accentuation of the J wave or to J point elevation. When epicardial repolarization precedes repolarization of the cells in the M and endocardial regions, the T wave remains positive. The result is a saddleback configuration of the repolarization waves Further accentuation of the notch may be accompanied by a prolongation of the epicardial AP 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 Brugada patients. A delay in epicardial activation may also contribute to inversion of the T wave. The downsloping ST-segment elevation 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 than major impulse conduction block in the right bundle.

A rigorous application 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. Moreover, attempts by Miyazaki and co-workers to record delayed activation of the RV in Brugada patients met with failure.

It is important to point out that although the typical Brugada morphology is present i, an arrhythmogenic substrate is absent. The arrhythmogenic substrate is thought to develop when a further shift in the balance of current leads to loss of the AP dome at some epicardial sites but not others .Loss of the AP dome in epicardium but not endocardium results in the development of a marked TDR and refractoriness, responsible for the development of a vulnerable window during which a premature impulse or extrasystole can induce a reentrant arrhythmia. Conduction of the AP 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 a very closely coupled extrasystole, which captures the vulnerable window across the wall, thus triggering a circus movement reentry in the form of VT/VF. 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 Q wave, which serves to accentuate the negative deflection of the inverted T wave, giving the ECG a more symmetrical appearance. This morphology is often observed in the clinic preceding the onset of polymorphic VT.


Studies involving the arterially perfused RV wedge preparation provide evidence in support of these hypotheses. A high resolution optical mapping system that allows simultaneous recording of transmembrane APs from 256 sites along the transmural surface of the arterially perfused canine RV wedge preparation has been used by Shimizu et al. to demonstrate that a steep repolarization gradient between the region at which the dome is lost and the region at which it is maintained is essential for the development of a closely coupled phase 2 reentrant extrasystole. This study also showed that reentry initially rotates in the epicardium and gradually shifts to a transmural orientation, responsible for nonsustained polymorphic VT or VF.


Gender based differences in the manifestations of brugada syndrome

Although the genetic mutation responsible for the Brugada syndrome is equally distributed between the sexes, the clinical phenotype is 8 to 10 times more prevalent in males than in females. The basis for this sex-related distinction has been shown to be due to a more prominent Ito-mediated AP notch in the RV epicardium of males versus females. The more prominent Ito causes the end of phase 1 of the RV epicardial AP to repolarize to more negative potentials in tissue and arterially perfused wedge preparations from males, facilitating loss of the AP dome and the development of phase 2 reentry and polymorphic VT.




Device Therapy

An ICD is the only proven effective device treatment for the disease Recommendations for ICD implantation and are summarized as follows:

–          Symptomatic patients displaying the Type 1 ST-segment elevation or Brugada ECG (either spontaneously or after sodium channel blockade) who present with aborted sudden death should receive an ICD as a Class I indication without additional need for EPS. Similar patients presenting with related symptoms such as syncope, seizure, or nocturnal agonal respiration should also undergo ICD implantation as a Class I indication after non-cardiac causes of these symptoms have been carefully ruled out. EPS is recommended in symptomatic patients only for the assessment of supraventricular arrhythmia.

–          Asymptomatic patients displaying a Brugada ECG (spontaneously or after sodium channel block) should undergo EPS if there is a family history of sudden cardiac death suspected to be due to Brugada syndrome. EPS may be justified when the family history is negative for sudden cardiac death if the Type 1 ST-segment elevation occurs spontaneously. If inducible for ventricular arrhythmia, the patient should receive an ICD. This was recommended as a Class IIa indication for patients presenting with a spontaneous Type I ST-segment elevation and as a Class IIb for patients who display a Type I ST-segment elevation only after sodium block challenge. More recent data (discussed above) have called these recommendations into question and suggest that it might be more appropriate to consider both as Class IIb indications.

–          Asymptomatic patients who have no family history and who develop a Type 1 ST-segment elevation only after sodium channel blockade should be closely followed-up. As additional data become available, these recommendations will no doubt require further fine-tuning.

Although arrhythmias and sudden cardiac death generally occur during sleep or at rest and have been associated with slow heart rates, a potential therapeutic role for cardiac pacing remains largely unexplored. Haissaguerre and co-workers reported that focal radiofrequency ablation aimed at eliminating the ventricular premature beats that trigger VT/VF in the Brugada syndrome may be useful in controlling arrhythmogenesis. However, data relative to a cryosurgical approach or the use of ablation therapy are very limited at this point in time.



Pharmacologic Approach to Therapy

ICD implantation is the mainstay of therapy for the Brugada syndrome. Although feasible, implantation is challenging in infants and is not an adequate solution for patients residing in regions of the world where an ICD is unaffordable. A pharmacologic solution is desirable as an alternative to device therapy in these cases, as well as in minimizing the firing of the ICD in patients with frequent events.

The quest for a pharmacologic treatment has been focused on rebalancing of the ion channel current 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. lists the various pharmacologic agents thus far investigated. Antiarrhythmic agents, such as amiodarone and β blockers, have been shown to be ineffective. Class IC antiarrhythmic drugs (such as flecainide and propafenone) and Class IA agents, such as procainamide, are contraindicated because of their effects to unmask the Brugada syndrome 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.

Because the presence of a prominent transient outward current, Ito, is fundamental to the mechanism underlying the Brugada syndrome, the most prudent general approach to therapy, regardless of the ionic or genetic basis for the disease, is to partially inhibit Ito. Cardioselective and Ito-specific blockers are not currently available. 4-aminopyridine is an agent that is ion-channel specific at low concentrations, but is not cardioselective in that it inhibits Ito in the nervous system. Although it is effective in suppressing arrhythmogenesis in wedge models of the Brugada syndrome it is unlikely to be of clinical benefit because of neurally mediated adverse effects.

An agent currently on the market in the United States and other regions of the world with significant Ito blocking properties is quinidine. Accordingly, we suggested several years ago that this agent may be of therapeutic value in the Brugada syndrome Quinidine has been shown to be effective in restoring the epicardial AP dome, thus normalizing the ST segment and preventing phase 2 reentry and polymorphic VT in experimental models of the Brugada syndrome. Clinical evidence of the effectiveness of quinidine in normalizing ST-segment elevation in patients with the Brugada syndrome has been reported as well Quinidine has also been reported to be effective in suppressing arrhythmogenesis in an infant too young to receive an ICD.

A prospective study of 25 Brugada syndrome patients orally administered quinidine bisulfate (1483 ± 240 mg), reported by Belhassen and Viskin, evaluated the effectiveness of quinidine in preventing inducible and spontaneous VF. There were 15 symptomatic patients (7 cardiac arrest survivors and 7 with unexplained syncope) and 10 asymptomatic patients. All 25 patients had inducible VF at baseline electrophysiological study. Quinidine prevented VF induction in 22 of the 25 patients (88%). After a follow-up period of 6 months to 22.2 years, all patients were alive. Of 19 patients treated with oral quinidine for 6 to 219 months (56 ± 67 months), none developed arrhythmic events. Administration of quinidine was associated with a 36% incidence of side effects, principally diarrhea, which resolved after drug discontinuation. The authors concluded that quinidine effectively suppresses VF induction as well as spontaneous arrhythmias in patients with Brugada syndrome, and may be useful as an adjunct to ICD therapy or as an alternative to ICD in cases in which an ICD is refused, is unaffordable, or under other circumstances in which ICD implantation is not feasible. These results are consistent with those reported for the same group in prior years and more recently by other investigators. The study by Hermida and co-workers was the first to report the results of prospective, although relatively small, clinical trials. A recent relatively small study by Mizusawa et al. showed that low-dose quinidine (300–600 mg) can prevent electrophysiologic induction of VF and has a potential as an adjunctive therapy for Brugada syndrome in patients with frequent ICD discharges. There is a clear need for a large, randomized, controlled clinical trial to assess the effectiveness of quinidine, preferably in patients with frequent events who have already received an ICD.

There is a clear need for a more cardioselective and Ito-specific blocker as an addition to the limited therapeutic armamentarium currently available to combat this disease. Another agent being considered for this purpose is the drug tedisamil, currently being evaluated for the treatment of atrial fibrillation. Tedisamil may be more potent than quinidine because it lacks the inward current blocking actions of quinidine, while potently blocking Ito.

Quinidine and tedisamil are both capable of suppressing the substrate and trigger for the Brugada syndrome via their inhibition of Ito. Both, however, also block IKr and thus have the potential to induce an acquired form of the long-QT syndrome. Thus, these agents may substitute one form of polymorphic VT for another, particularly under conditions that promote TdP, such as bradycardia and hypokalemia. This effect of quinidine is minimized at high plasma levels, because at these concentrations quinidine block of INa counters the effect of IKr block to increase TDR, the substrate for the development of TdP arrhythmias. High doses of quinidine (1,000–1,500 mg/day) are recommended in order to effect Ito block, without inducing TdP.

Another potential therapeutic candidate is an agent reported to be a relatively selective Ito and IKur blocker, AVE0118,  shows the effect of AVE0118 to normalize the ECG and suppress phase 2 reentry in a wedge model of the Brugada syndrome. This drug has the advantage that it does not block IKr, and therefore does not prolong the QT interval or have the potential to induce TdP. The disadvantage of this particular drug is that it undergoes first-pass hepatic metabolism and is therefore not effective with oral administration.

Appropriate clinical trials are needed to establish the effectiveness of all of the above pharmacologic agents, as well as the possible role of pacemakers.

Agents that increase the calcium current, such as β-adrenergic agents like isoproterenol, are useful as well. Isoproterenol, sometimes in combination with quinidine, has been shown to be effective in normalizing ST-segment elevation in patients with the Brugada syndrome and in controlling electrical storms, particularly in children. A recent addition to the pharmacological armamentarium is the phosphodiesterase III inhibitor, cilostazol, which normalizes the ST segment, most likely by augmenting calcium current (ICa), as well as by reducing Ito secondary to an increase in heart rate.

Another pharmacologic approach is to augment a component of INa that is active during phase 1 of the epicardial AP. Dimethyl Lithospermate B (dmLSB) is an extract of Danshen, a traditional Chinese herbal remedy, which slows inactivation of INa, leading to increased inward current during the early phases of the AP. shows the effectiveness of dmLSB in eliminating the arrhythmogenic substrate responsible for the Brugada syndrome in three different experimental models of the syndrome. The Brugada syndrome phenotype was created in canine arterially perfused RV wedge preparations using either terfenadine or verapamil to inhibit INa and ICa, or pinacidil to activate IK–ATP. Terfenadine, verapamil, and pinacidil each induced all-or-none repolarization at some epicardial sites but not others, leading to ST-segment elevation, as well as an increase in both EDR and TDR from 12.9 ± 9.6 ms to 107.0 ± 54.8 ms and 22.4 ± 8.1 ms to 82.2 ± 37.4 ms, respectively (P < 0.05, n = 9). Under these conditions, phase 2 reentry developed, as the epicardial AP dome propagated from sites where it was maintained to sites at which it was lost, generating closely coupled extrasystoles and VT/VF. Addition of dmLSB (10 μM) to the coronary perfusate restored the epicardial AP dome, reduced both EDR and TDR, and abolished phase 2 reentry-induced extrasystoles and VT/VF in 9/9 preparations. Our data suggest that dmLSB may be a candidate for pharmacologic treatment of Brugada syndrome in cases in which an ICD is not feasible or affordable, or as an adjunct to ICD use.